Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting sex steroid biosynthesis for breast and prostate cancer therapy

Nature Reviews Cancer volume 23, pages 686–709 (2023)Cite this article

Subjects

Abstract

Sex steroids, such as androgens and oestrogens, are hormones that primarily regulate the physiology of reproductive organs and maintain reproductive capacity in both men and women, respectively. Later in life, these sex steroids can become major promoters of the growth of cancer in the reproductive tissues, such as the breast and prostate, with breast cancer being the most common cancer in women and prostate cancer being the second most common cancer in men. Oestrogens and androgens act via specific receptor proteins that act as steroid-activated transcription factors. Accordingly, all current endocrine therapies for breast and prostate cancer target steroid–receptor interactions either directly or indirectly. These therapies encompass compounds that inhibit gonadotropin-regulated steroid biosynthesis in the gonads, antagonists and degraders of oestrogen and androgen receptors, and inhibitors of enzymes of oestrogen and androgen biosynthesis. Such enzyme inhibitors can reduce the concentration of potent oestrogens and androgens and their precursors in the tumours by blocking their gonadal and adrenal production, by hindering the activation of the blood-transported precursors within the tumours and/or by inhibiting any local de novo steroid biosynthesis in the tumours. Some well-characterized inhibitors of enzymes of the classical biosynthesis routes of oestrogens and androgens are used in the treatment of breast and prostate cancer, and novel compounds are in development. However, it is likely that not all enzymes involved in sex steroid biosynthesis have been discovered. Furthermore, novel biologically active sex steroids, such as 11-oxygenated androgens, have been more recently identified. Accordingly, so-far-unidentified targets and novel mechanisms for inhibiting sex steroid biosynthesis are expected to provide further tools for more efficient therapies for sex steroid-dependent breast and prostate cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Androgen and oestrogen receptors are hormone-activated transcription factors.
Fig. 2: Androgens and oestrogens act via endocrine, paracrine and intracrine mechanisms.
Fig. 3: Various enzymes of androgen and oestrogen biosynthesis from cholesterol are utilized as drug targets.
Fig. 4: Androgen and oestrogen biosynthesis can be inhibited at multiple levels of the biosynthesis pathway.

References

  1. Carson-Jurica, M. A., Schrader, W. T. & O’Malley, B. W. Steroid receptor family: structure and functions. Endocr. Rev. 11, 201–220 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Simpson, E. R. et al. Estrogen—the good, the bad, and the unexpected. Endocr. Rev. 26, 322–330 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Russell, N. & Grossmann, M. Mechanisms in endocrinology: estradiol as a male hormone. Eur. J. Endocrinol. 181, R23–R43 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Walters, K. A., Simanainen, U. & Gibson, D. A. Androgen action in female reproductive physiology. Curr. Opin. Endocrinol. Diabetes Obes. 23, 291–296 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Naamneh Elzenaty, R., du Toit, T. & Fluck, C. E. Basics of androgen synthesis and action. Best. Pract. Res. Clin. Endocrinol. Metab. 36, 101665 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Tsai, M. J. & O’Malley, B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem. 63, 451–486 (1994). This study is one of the first reviews describing the mechanisms by which steroid receptors modulate transcription at the target cell level.

    Article  CAS  PubMed  Google Scholar 

  7. Ruff, M., Gangloff, M., Wurtz, J. M. & Moras, D. Estrogen receptor transcription and transactivation: structure–function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res. 2, 353–359 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shiau, A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998). This work is one of the initial studies showing the differential structure of the steroid receptor after binding an agonist or a SERM compound.

    Article  CAS  PubMed  Google Scholar 

  9. El Kharraz, S. et al. The androgen receptor depends on ligand-binding domain dimerization for transcriptional activation. EMBO Rep. 22, e52764 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Heemers, H. V. & Tindall, D. J. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr. Rev. 28, 778–808 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33–43 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Sahu, B. et al. Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J. 30, 3962–3976 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Le Dily, F. et al. Hormone-control regions mediate steroid receptor-dependent genome organization. Genome Res. 29, 29–39 (2019). This study is one of the more recent showing the role of steroid receptors in organizing the genome structure and facilitating steroid-induced transcriptional changes.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Paakinaho, V. & Palvimo, J. J. Genome-wide crosstalk between steroid receptors in breast and prostate cancers. Endocr. Relat. Cancer 28, R231–R250 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mauvais-Jarvis, F., Lange, C. A. & Levin, E. R. Membrane-initiated estrogen, androgen and progesterone receptor signaling in health and disease. Endocr. Rev. 43, 720–742 (2021).

    Article  PubMed Central  Google Scholar 

  16. Zhao, L., Zhou, S. & Gustafsson, J. A. Nuclear receptors: recent drug discovery for cancer therapies. Endocr. Rev. 40, 1207–1249 (2019).

    PubMed  Google Scholar 

  17. Westaby, D. et al. A new old target: androgen receptor signaling and advanced prostate cancer. Annu. Rev. Pharmacol. Toxicol. 62, 131–153 (2022).

    Article  PubMed  Google Scholar 

  18. Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 9, 401–406 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004).

    Article  PubMed  Google Scholar 

  20. Howlader, N. et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl Cancer Inst. 106, dju055 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Anderson, W. F., Chatterjee, N., Ershler, W. B. & Brawley, O,W. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res. Treat. 76, 27–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Article  PubMed  Google Scholar 

  23. Puhalla, S., Bhattacharya, S. & Davidson, N. E. Hormonal therapy in breast cancer: a model disease for the personalization of cancer care. Mol. Oncol. 6, 222–236 (2012). This review is complementary to the present Review, describing the development of hormonal therapies specifically for breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Desai, K., McManus, J. M. & Sharifi, N. Hormonal therapy for prostate cancer. Endocr. Rev. 42, 354–373 (2021). This review is complementary to the present Review, describing the development of hormonal therapies specifically for prostate cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jordan, V. C. The science of selective estrogen receptor modulators: concept to clinical practice. Clin. Cancer Res. 12, 5010–5013 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Nyquist, M. D. et al. Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth. J. Clin. Invest. 131, e146777 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McDonnell, D. P., Wardell, S. E., Chang, C. Y. & Norris, J. D. Next-generation endocrine therapies for breast cancer. J. Clin. Oncol. 39, 1383–1388 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Swaby, R. F., Sharma, C. G. & Jordan, V. C. SERMs for the treatment and prevention of breast cancer. Rev. Endocr. Metab. Disord. 8, 229–239 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Mori, K. et al. Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Int. J. Clin. Oncol. 25, 1892–1900 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zanger, U. M. & Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 138, 103–141 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Jornvall, H. et al. Short-chain dehydrogenases/reductases (SDR). Biochemistry 34, 6003–6013 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Penning, T. M., Wangtrakuldee, P. & Auchus, R. J. Structural and functional biology of aldo-keto reductase steroid-transforming enzymes. Endocr. Rev. 40, 447–475 (2019).

    Article  PubMed  Google Scholar 

  33. Nelson, D. R. et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14, 1–18 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Penning, T. M. & Drury, J. E. Human aldo-keto reductases: function, gene regulation, and single nucleotide polymorphisms. Arch. Biochem. Biophys. 464, 241–250 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Persson, B. & Kallberg, Y. Classification and nomenclature of the superfamily of short-chain dehydrogenases/reductases (SDRs). Chem. Biol. Interact. 202, 111–115 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Miller, W. L. & Auchus, R. J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32, 81–151 (2011). This work extensively reviews the basic principles of sex steroid synthesis.

    Article  CAS  PubMed  Google Scholar 

  37. Sharifi, N., Gulley, J. L. & Dahut, W. L. Androgen deprivation therapy for prostate cancer. J. Am. Med. Assoc. 294, 238–244 (2005).

    Article  CAS  Google Scholar 

  38. Simpson, E. R. Sources of estrogen and their importance. J. Steroid Biochem. Mol. Biol. 86, 225–230 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Kaprara, A. & Huhtaniemi, I. T. The hypothalamus–pituitary–gonad axis: tales of mice and men. Metabolism 86, 3–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Fauser, B. C. & Van Heusden, A. M. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr. Rev. 18, 71–106 (1997).

    CAS  PubMed  Google Scholar 

  41. Miller, W. L. The hypothalamic–pituitary–adrenal axis: a brief history. Horm. Res. Paediatr. 89, 212–223 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Kirschner, M. A. & Bardin, C. W. Androgen production and metabolism in normal and virilized women. Metabolism 21, 667–688 (1972).

    Article  CAS  PubMed  Google Scholar 

  43. Puurunen, J. et al. Adrenal androgen production capacity remains high up to menopause in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 94, 1973–1978 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Abraham, G. E. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J. Clin. Endocrinol. Metab. 39, 340–346 (1974).

    Article  CAS  PubMed  Google Scholar 

  45. Labrie, F. Intracrinology. Mol. Cell Endocrinol. 78, C113–C118 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Turcu, A. F., Rege, J., Auchus, R. J. & Rainey, W. E. 11-Oxygenated androgens in health and disease. Nat. Rev. Endocrinol. 16, 284–296 (2020). This work comprehensively reviews the newly recognized potent 11-oxygenated androgens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pretorius, E. et al. 11-Ketotestosterone and 11-ketodihydrotestosterone in castration resistant prostate cancer: potent androgens which can no longer be ignored. PLoS ONE 11, e0159867 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Blouin, K. et al. Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women. Am. J. Physiol. Endocrinol. Metab. 288, E398–E404 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. du Toit, T. & Swart, A. C. The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone. J. Steroid Biochem. Mol. Biol. 196, 105497 (2020).

    Article  PubMed  Google Scholar 

  50. Barnard, M. et al. 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): implications for castration resistant prostate cancer. J. Steroid Biochem. Mol. Biol. 183, 192–201 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Snaterse, G. et al. 11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration. JCI Insight 6, e148507 (2021).

    PubMed  PubMed Central  Google Scholar 

  52. Rainey, W. E. & Nakamura, Y. Regulation of the adrenal androgen biosynthesis. J. Steroid Biochem. Mol. Biol. 108, 281–286 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Labrie, F. et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids 63, 322–328 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Bianchini, F., Kaaks, R. & Vainio, H. Overweight, obesity, and cancer risk. Lancet Oncol. 3, 565–574 (2002).

    Article  PubMed  Google Scholar 

  55. Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011). This paper summarizes the obesity-related signalling mechanisms that promote cancer development.

    Article  CAS  PubMed  Google Scholar 

  56. Allott, E. H., Masko, E. M. & Freedland, S. J. Obesity and prostate cancer: weighing the evidence. Eur. Urol. 63, 800–809 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Friedenreich, C. M., Ryder-Burbidge, C. & McNeil, J. Physical activity, obesity and sedentary behavior in cancer etiology: epidemiologic evidence and biologic mechanisms. Mol. Oncol. 15, 790–800 (2021).

    Article  PubMed  Google Scholar 

  58. Baglietto, L. et al. Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition. Breast Cancer Res. Treat. 115, 171–179 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Mayneris-Perxachs, J. et al. Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status. Microbiome 8, 136 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, L. et al. The expression of sex steroid synthesis and inactivation enzymes in subcutaneous adipose tissue of PCOS patients. J. Steroid Biochem. Mol. Biol. 132, 120–126 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Tchernof, A. et al. Updated survey of the steroid-converting enzymes in human adipose tissues. J. Steroid Biochem. Mol. Biol. 147, 56–69 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Price, T. et al. Determination of aromatase cytochrome P450 messenger ribonucleic acid in human breast tissue by competitive polymerase chain reaction amplification. J. Clin. Endocrinol. Metab. 74, 1247–1252 (1992).

    CAS  PubMed  Google Scholar 

  63. Zhao, H., Zhou, L., Shangguan, A. J. & Bulun, S. E. Aromatase expression and regulation in breast and endometrial cancer. J. Mol. Endocrinol. 57, R19–R33 (2016). This review summarizes the molecular mechanisms that regulate the aromatase gene in the gonads and the breast; it provides an example of the differential regulatory mechanisms of endocrine and paracrine sex steroid synthesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bulun, S. E., Chen, D., Moy, I., Brooks, D. C. & Zhao, H. Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol. Metab. 23, 83–89 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Santen, R. J., Brodie, H., Simpson, E. R., Siiteri, P. K. & Brodie, A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr. Rev. 30, 343–375 (2009). This work comprehensively reviews the path to the development of aromatase inhibitors, which have had a great impact on breast cancer treatment.

    Article  CAS  PubMed  Google Scholar 

  66. Zomzely, C., Asti, R. & Mayer, J. Storage of steroid hormones by adipose tissue in two experimental obesities. Science 129, 1546–1547 (1959).

    Article  CAS  PubMed  Google Scholar 

  67. Collden, H. et al. Comprehensive sex steroid profiling in multiple tissues reveals novel insights in sex steroid distribution in male mice. Endocrinology 163, bqac001 (2022). This study provides a tissue atlas for sex steroids in male mice and defines the adipose tissue as a reserve source of potent androgens and progesterone in this preclinical animal model.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Feher, T. & Bodrogi, L. A comparative study of steroid concentrations in human adipose tissue and the peripheral circulation. Clin. Chim. Acta 126, 135–141 (1982).

    Article  CAS  PubMed  Google Scholar 

  69. Belanger, C., Luu-The, V., Dupont, P. & Tchernof, A. Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Horm. Metab. Res. 34, 737–745 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Falk, R. T. et al. Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women. Breast Cancer Res. Treat. 131, 287–294 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Li, J., Papadopoulos, V. & Vihma, V. Steroid biosynthesis in adipose tissue. Steroids 103, 89–104 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Vihma, V. & Tikkanen, M. J. Fatty acid esters of steroids: synthesis and metabolism in lipoproteins and adipose tissue. J. Steroid Biochem. Mol. Biol. 124, 65–76 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Larner, J. M., Shackleton, C. H., Roitman, E., Schwartz, P. E. & Hochberg, R. B. Measurement of estradiol-17-fatty acid esters in human tissues. J. Clin. Endocrinol. Metab. 75, 195–200 (1992).

    CAS  PubMed  Google Scholar 

  74. Del Castillo-Izquierdo, A., Mayneris-Perxachs, J. & Fernandez-Real, J. M. Bidirectional relationships between the gut microbiome and sexual traits. Am. J. Physiol. Cell Physiol. https://doi.org/10.1152/ajpcell.00116.2022 (2022).

  75. Clarke, G. et al. Minireview: Gut microbiota: the neglected endocrine organ. Mol. Endocrinol. 28, 1221–1238 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Gloux, K. et al. A metagenomic β-glucuronidase uncovers a core adaptive function of the human intestinal microbiome. Proc. Natl Acad. Sci. USA 108, 4539–4546 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Flores, R. et al. Association of fecal microbial diversity and taxonomy with selected enzymatic functions. PLoS ONE 7, e39745 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lombardi, P., Goldin, B., Boutin, E. & Gorbach, S. L. Metabolism of androgens and estrogens by human fecal microorganisms. J. Steroid Biochem. 9, 795–801 (1978).

    Article  CAS  PubMed  Google Scholar 

  79. Pernigoni, N. et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 374, 216–224 (2021). This study demonstrates the ability of the gut microbiota to metabolize steroids and modulate androgen action and androgen-dependent tumour growth in a mouse model of CRPC.

    Article  CAS  PubMed  Google Scholar 

  80. Garcia-Gomez, E., Gonzalez-Pedrajo, B. & Camacho-Arroyo, I. Role of sex steroid hormones in bacterial–host interactions. Biomed. Res. Int. 2013, 928290 (2013).

    Article  PubMed  Google Scholar 

  81. Szaleniec, M., Wojtkiewicz, A. M., Bernhardt, R., Borowski, T. & Donova, M. Bacterial steroid hydroxylases: enzyme classes, their functions and comparison of their catalytic mechanisms. Appl. Microbiol. Biotechnol. 102, 8153–8171 (2018). This review introduces the various bacterial enzymes capable of steroid metabolism, although their presence and role in the human gut microbiota needs further exploration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Collden, H. et al. The gut microbiota is a major regulator of androgen metabolism in intestinal contents. Am. J. Physiol. Endocrinol. Metab. 317, E1182–E1192 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang, X. et al. Sex- and age-related trajectories of the adult human gut microbiota shared across populations of different ethnicities. Nat. Aging 1, 87–100 (2021).

    Article  PubMed  Google Scholar 

  84. Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Matsushita, M. et al. Firmicutes in gut microbiota correlate with blood testosterone levels in elderly men. World J. Mens. Health 40, 517–525 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Matsushita, M. et al. The gut microbiota associated with high-Gleason prostate cancer. Cancer Sci. 112, 3125–3135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kalinen, S. et al. Gut microbiota affects prostate cancer risk through steroid hormone biosynthesis. Preprint at medRxiv https://doi.org/10.1101/2021.08.19.21262274 (2022).

  88. Fujita, K. et al. Gut microbiome and prostate cancer. Int. J. Urol. 29, 793–798 (2022).

    Article  CAS  PubMed  Google Scholar 

  89. Terrisse, S. et al. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment. Cell Death Differ. 28, 2778–2796 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Trapani, L., Segatto, M. & Pallottini, V. Regulation and deregulation of cholesterol homeostasis: the liver as a metabolic “power station”. World J. Hepatol. 4, 184–190 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Schiffer, L. et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review. J. Steroid Biochem. Mol. Biol. 194, 105439 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gwynne, J. T. & Strauss, J. F. 3rd The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr. Rev. 3, 299–329 (1982).

    Article  CAS  PubMed  Google Scholar 

  93. Hammond, G. L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. J. Endocrinol. 230, R13–R25 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bikle, D. D. The free hormone hypothesis: when, why, and how to measure the free hormone levels to assess vitamin D, thyroid, sex hormone, and cortisol status. JBMR 5, e10418 (2021).

    CAS  Google Scholar 

  95. Thigpen, A. E. et al. Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression. J. Clin. Invest. 92, 903–910 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Normington, K. & Russell, D. W. Tissue distribution and kinetic characteristics of rat steroid 5α-reductase isozymes. Evidence for distinct physiological functions. J. Biol. Chem. 267, 19548–19554 (1992).

    Article  CAS  PubMed  Google Scholar 

  97. Amai, K. et al. Quantitative analysis of mRNA expression levels of aldo-keto reductase and short-chain dehydrogenase/reductase isoforms in human livers. Drug Metab. Pharmacokinet. 35, 539–547 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Wilson, J. D. & Roehrborn, C. Long-term consequences of castration in men: lessons from the Skoptzy and the eunuchs of the Chinese and Ottoman courts. J. Clin. Endocrinol. Metab. 84, 4324–4331 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Andersson, S., Berman, D. M., Jenkins, E. P. & Russell, D. W. Deletion of steroid 5α-reductase 2 gene in male pseudohermaphroditism. Nature 354, 159–161 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Brinkmann, A. O. Molecular basis of androgen insensitivity. Mol. Cell Endocrinol. 179, 105–109 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Cunha, G. R. & Chung, L. W. Stromal–epithelial interactions—I. Induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J. Steroid Biochem. 14, 1317–1324 (1981).

    Article  CAS  PubMed  Google Scholar 

  102. Cunha, G. R. et al. Development of the human prostate. Differentiation 103, 24–45 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Brisken, C. & O’Malley, B. Hormone action in the mammary gland. Cold Spring Harb. Perspect. Biol. 2, a003178 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Burstein, H. J. et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J. Clin. Oncol. 34, 1689–1701 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. Wong, Y. N., Ferraldeschi, R., Attard, G. & de Bono, J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat. Rev. Clin. Oncol. 11, 365–376 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Bui, K. T., Willson, M. L., Goel, S., Beith, J. & Goodwin, A. Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer. Cochrane Database Syst. Rev. 3, CD013538 (2020).

    PubMed  Google Scholar 

  107. Schroder, F., Crawford, E. D., Axcrona, K., Payne, H. & Keane, T. E. Androgen deprivation therapy: past, present and future. BJU Int. 109, 1–12 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Huerta-Reyes, M. et al. Treatment of breast cancer with gonadotropin-releasing hormone analogs. Front. Oncol. 9, 943 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Clarke, R., Tyson, J. J. & Dixon, J. M. Endocrine resistance in breast cancer—an overview and update. Mol. Cell Endocrinol. 418 Pt 3, 220–234 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sharifi, N. Mechanisms of androgen receptor activation in castration-resistant prostate cancer. Endocrinology 154, 4010–4017 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Stuchbery, R., McCoy, P. J., Hovens, C. M. & Corcoran, N. M. Androgen synthesis in prostate cancer: do all roads lead to Rome? Nat. Rev. Urol. 14, 49–58 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Lonning, P. E. et al. Recent data on intratumor estrogens in breast cancer. Steroids 76, 786–791 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Lonning, P. E. Estradiol measurement in translational studies of breast cancer. Steroids 99, 26–31 (2015).

    Article  PubMed  Google Scholar 

  114. Santen, R. J. et al. Enzymatic control of estrogen production in human breast cancer: relative significance of aromatase versus sulfatase pathways. Ann. N.Y. Acad. Sci. 464, 126–137 (1986). This comprehensive review describes the basis for the strategy used to reduce breast cancer growth by inhibiting local production of oestradiol in tumours.

    Article  CAS  PubMed  Google Scholar 

  115. Knuuttila, M. et al. Intratumoral androgen levels are linked to TMPRSS2–ERG fusion in prostate cancer. Endocr. Relat. Cancer 25, 807–819 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Page, S. T. et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J. Clin. Endocrinol. Metab. 91, 3850–3856 (2006). This study shows that chemical castration does not reduce intra-prostatic androgen levels to the same extent as that observed in the circulation, and that androgen action in the prostate is still present.

    Article  CAS  PubMed  Google Scholar 

  117. Montgomery, R. B. et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68, 4447–4454 (2008). This study presents data that suggest metastatic prostate cancers may maintain intra-tumoural androgens by expressing enzymes involved in intracrine steroidogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B. & Mohler, J. L. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11, 4653–4657 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Geller, J. et al. DHT concentrations in human prostate cancer tissue. J. Clin. Endocrinol. Metab. 46, 440–444 (1978).

    Article  CAS  PubMed  Google Scholar 

  120. Sharifi, N. & Auchus, R. J. Steroid biosynthesis and prostate cancer. Steroids 77, 719–726 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Barnard, M., Mostaghel, E. A., Auchus, R. J. & Storbeck, K. H. The role of adrenal derived androgens in castration resistant prostate cancer. J. Steroid Biochem. Mol. Biol. 197, 105506 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Stanbrough, M. et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66, 2815–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Hofland, J. et al. Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 70, 1256–1264 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Locke, J. A. et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 68, 6407–6415 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Armandari, I., Hamid, A. R., Verhaegh, G. & Schalken, J. Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy. Prostate Int. 2, 105–113 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Cai, C. & Balk, S. P. Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr. Relat. Cancer 18, R175–R182 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Tietz, K. T. & Dehm, S. M. Androgen receptor variants: RNA-based mechanisms and therapeutic targets. Hum. Mol. Genet. 29, R19–R26 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Luo, J. et al. Role of androgen receptor variants in prostate cancer: report from the 2017 Mission Androgen Receptor Variants meeting. Eur. Urol. 73, 715–723 (2018).

    Article  PubMed  Google Scholar 

  129. Dunn, B. K. & Ford, L. G. Hormonal interventions to prevent hormonal cancers: breast and prostate cancers. Eur. J. Cancer Prev. 16, 232–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Huirne, J. A. & Lambalk, C. B. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 358, 1793–1803 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Klotz, L. et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 102, 1531–1538 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Sayyid, R. K. et al. A phase II, randomized, open-label study of neoadjuvant degarelix versus LHRH agonist in prostate cancer patients prior to radical prostatectomy. Clin. Cancer Res. 23, 1974–1980 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Eckstein, N. & Haas, B. Clinical pharmacology and regulatory consequences of GnRH analogues in prostate cancer. Eur. J. Clin. Pharmacol. 70, 791–798 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Trachtenberg, J. et al. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J. Urol. 167, 1670–1674 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Ferraro, E., Trapani, D., Marrucci, E. & Curigliano, G. Evaluating triptorelin as a treatment option for breast cancer. Expert. Opin. Pharmacother. 20, 1809–1818 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Dellapasqua, S. et al. Neoadjuvant degarelix versus triptorelin in premenopausal patients who receive letrozole for locally advanced endocrine-responsive breast cancer: a randomized phase II trial. J. Clin. Oncol. 37, 386–395 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Morote, J. et al. Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy. BJU Int. 103, 332–335 (2009); discussion 103, 335 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Loriot, Y. et al. Management of non-metastatic castrate-resistant prostate cancer: a systematic review. Cancer Treat. Rev. 70, 223–231 (2018).

    Article  PubMed  Google Scholar 

  139. Kirby, M., Hirst, C. & Crawford, E. D. Characterising the castration-resistant prostate cancer population: a systematic review. Int. J. Clin. Pract. 65, 1180–1192 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Crawford, E. D. et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N. Engl. J. Med. 321, 419–424 (1989).

    Article  CAS  PubMed  Google Scholar 

  141. Holzbeierlein, J. et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol. 164, 217–227 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Attard, G. et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J. Clin. Oncol. 26, 4563–4571 (2008). This work is one of the early clinical studies showing the dramatic reduction of circulating testosterone and its precursors, androstenedione and DHEA, after chemically castrated men were treated with a combination treatment that included a CYP17A1 inhibitor. The treatment showed anti-tumour activity and led to further clinical trials evaluating the androgen dependency of CRPC.

    Article  CAS  PubMed  Google Scholar 

  143. Parker, C. et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 31, 1119–1134 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Fizazi, K. et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 20, 686–700 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. James, N. D. et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N. Engl. J. Med. 377, 338–351 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Chi, K. N. et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J. Clin. Oncol. 39, 2294–2303 (2021).

    Article  CAS  PubMed  Google Scholar 

  147. Armstrong, A. J. et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J. Clin. Oncol. 37, 2974–2986 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Attard, G. et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 399, 447–460 (2022). As part of a long-term clinical trial, this study reports the efficacy of abiraterone in the treatment of men with high-risk non-metastatic prostate cancer in combination with ADT and enzalutamide compared with ADT and enzalutamide alone.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Saad, F. et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 22, 1541–1559 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kase, A. M., Copland Iii, J. A. & Tan, W. Novel therapeutic strategies for CDK4/6 inhibitors in metastatic castrate-resistant prostate cancer. Onco Targets Ther. 13, 10499–10513 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Goel, S., Bergholz, J. S. & Zhao, J. J. Targeting CDK4 and CDK6 in cancer. Nat. Rev. Cancer 22, 356–372 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/study/NCT05288166 (2022).

  153. Baum, M. et al. Adjuvant goserelin in pre-menopausal patients with early breast cancer: results from the ZIPP study. Eur. J. Cancer 42, 895–904 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 23, 382–392 (2022).

    Article  Google Scholar 

  155. Lu, Y. S. et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2− advanced breast cancer in MONALEESA-7: a phase III randomized clinical trial. Clin. Cancer Res. 28, 851–859 (2022).

    Article  CAS  PubMed  Google Scholar 

  156. Neven, P. et al. Abemaciclib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2−negative advanced breast cancer in premenopausal women: subgroup analysis from the MONARCH 2 trial. Breast Cancer Res. 23, 87 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Loibl, S. et al. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist 22, 1028–1038 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Potter, G. A., Barrie, S. E., Jarman, M. & Rowlands, M. G. Novel steroidal inhibitors of human cytochrome P45017α (17α-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J. Med. Chem. 38, 2463–2471 (1995).

    Article  CAS  PubMed  Google Scholar 

  159. Attard, G., Belldegrun, A. S. & de Bono, J. S. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 96, 1241–1246 (2005).

    Article  PubMed  Google Scholar 

  160. Barrie, S. E. et al. Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P450(17α) inhibitors. J. Steroid Biochem. Mol. Biol. 60, 347–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  161. Jarman, M., Barrie, S. E. & Llera, J. M. The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017α by abiraterone (17-(3-pyridyl)androsta-5,16-dien-3beta-ol) and related steroidal inhibitors. J. Med. Chem. 41, 5375–5381 (1998).

    Article  CAS  PubMed  Google Scholar 

  162. Sakai, M., Martinez-Arguelles, D. B., Aprikian, A. G., Magliocco, A. M. & Papadopoulos, V. De novo steroid biosynthesis in human prostate cell lines and biopsies. Prostate 76, 575–587 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. Cai, C. et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 71, 6503–6513 (2011). This study used prostate cancer xenografts to show that de novo intra-tumoural steroid synthesis is a mechanism that contributes to AR-dependent resistance to CYP17A1 inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011). This study is the first report of the efficacy of the CYP17A1 inhibitor (abiraterone) in combination with the glucocorticoid prednisone in increasing overall survival of men with CRPC compared with the placebo of prednisone only.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Mostaghel, E. A. et al. Circulating and intratumoral adrenal androgens correlate with response to abiraterone in men with castration-resistant prostate cancer. Clin. Cancer Res. 27, 6001–6011 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Auchus, R. J., Yu, M. K., Nguyen, S. & Mundle, S. D. Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer. Oncologist 19, 1231–1240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mostaghel, E. A. et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin. Cancer Res. 17, 5913–5925 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chen, E. J. et al. Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin. Cancer Res. 21, 1273–1280 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Hou, Z. et al. Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer. Cell Rep. Med. 3, 100561 (2022). This study shows an association between high circulating progesterone levels and poor clinical outcomes after abiraterone treatment in patients with prostate cancer and proposes that progesterone might be an oncogenic hormone in the prostate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bird, I. M. & Abbott, D. H. The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J. Steroid Biochem. Mol. Biol. 163, 136–146 (2016). This review outlines the potential of the still-ongoing generation of drugs selective for the 17,20 lyase activity of CYP17A1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Udhane, S. S., Dick, B., Hu, Q., Hartmann, R. W. & Pandey, A. V. Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis. Biochem. Biophys. Res. Commun. 477, 1005–1010 (2016). This study shows the potential to synthesize CYP17A1 inhibitors that prefer to block the 17α-hydroxylase–C17,20-lyase reaction over that of the 17α-hydroxylase, and thereby reduce the impact on adrenal steroid synthesis.

    Article  CAS  PubMed  Google Scholar 

  172. Yu, Z. et al. Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor. Clin. Cancer Res. 20, 4075–4085 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kwegyir-Afful, A. K., Ramalingam, S., Purushottamachar, P., Ramamurthy, V. P. & Njar, V. C. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget 6, 27440–27460 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Toren, P. J. et al. Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer. Mol. Cancer Ther. 14, 59–69 (2015).

    Article  CAS  PubMed  Google Scholar 

  175. Taplin, M. E. et al. Androgen receptor modulation optimized for response-splice variant: a phase 3, randomized trial of galeterone versus enzalutamide in androgen receptor splice variant-7-expressing metastatic castration-resistant prostate cancer. Eur. Urol. 76, 843–851 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Madan, R. A. et al. Phase 2 study of seviteronel (INO-464) in patients with metastatic castration-resistant prostate cancer after enzalutamide treatment. Clin. Genitourin. Cancer 18, 258–267.e1 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Agarwal, N. et al. Orteronel for metastatic hormone-sensitive prostate cancer: a multicenter, randomized, open-label phase III trial (SWOG-1216). J. Clin. Oncol. 40, 3301–3309 (2022).

    Article  CAS  PubMed  Google Scholar 

  178. Fizazi, K. et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J. Clin. Oncol. 33, 723–731 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Saad, F. et al. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 16, 338–348 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Kwegyir-Afful, A. K. et al. Galeterone and the next generation galeterone analogs, VNPP414 and VNPP433-3β exert potent therapeutic effects in castration-/drug-resistant prostate cancer preclinical models in vitro and in vivo. Cancers 11, 1637 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bonnefoi, H. et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12−1). Ann. Oncol. 27, 812–818 (2016).

    Article  CAS  PubMed  Google Scholar 

  182. Grellety, T. et al. Enhancing abiraterone acetate efficacy in androgen receptor-positive triple-negative breast cancer: Chk1 as a potential target. Clin. Cancer Res. 25, 856–867 (2019).

    Article  CAS  PubMed  Google Scholar 

  183. Yardley, D. A. et al. A phase II study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer (MBC). Clin. Breast Cancer 22, 269–278 (2022).

    Article  CAS  PubMed  Google Scholar 

  184. Lonning, P. E. et al. Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status. J. Steroid Biochem. Mol. Biol. 117, 31–41 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Folkerd, E. J., Martin, L. A., Kendall, A. & Dowsett, M. The relationship between factors affecting endogenous oestradiol levels in postmenopausal women and breast cancer. J. Steroid Biochem. Mol. Biol. 102, 250–255 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. Molehin, D., Filleur, S. & Pruitt, K. Regulation of aromatase expression: potential therapeutic insight into breast cancer treatment. Mol. Cell Endocrinol. 531, 111321 (2021).

    Article  CAS  PubMed  Google Scholar 

  187. Ma, C. X., Reinert, T., Chmielewska, I. & Ellis, M. J. Mechanisms of aromatase inhibitor resistance. Nat. Rev. Cancer 15, 261–275 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Miki, Y. et al. Aromatase localization in human breast cancer tissues: possible interactions between intratumoral stromal and parenchymal cells. Cancer Res. 67, 3945–3954 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Hanker, A. B., Sudhan, D. R. & Arteaga, C. L. Overcoming endocrine resistance in breast cancer. Cancer Cell 37, 496–513 (2020). This work comprehensively reviews the mechanisms of endocrine treatments and the development of resistance to them, as well as possibilities for overcoming this resistance in breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Brodie, A. M. Aromatase inhibitors in the treatment of breast cancer. J. Steroid Biochem. Mol. Biol. 49, 281–287 (1994).

    Article  CAS  PubMed  Google Scholar 

  191. Chumsri, S., Howes, T., Bao, T., Sabnis, G. & Brodie, A. Aromatase, aromatase inhibitors, and breast cancer. J. Steroid Biochem. Mol. Biol. 125, 13–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Briest, S. & Davidson, N. E. Aromatase inhibitors for breast cancer. Rev. Endocr. Metab. Disord. 8, 215–228 (2007).

    Article  CAS  PubMed  Google Scholar 

  193. Simpson, E. R. & Dowsett, M. Aromatase and its inhibitors: significance for breast cancer therapy. Recent. Prog. Horm. Res. 57, 317–338 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Toy, W. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45, 1439–1445 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Robinson, D. R. et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45, 1446–1451 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Piezzo, M. et al. Progression-free survival and overall survival of CDK 4/6 inhibitors plus endocrine therapy in metastatic breast cancer: a systematic review and meta-analysis. Int. J. Mol. Sci. 21, 6400 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  198. Jiang, Z. et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 806–815 (2019).

    Article  CAS  PubMed  Google Scholar 

  199. Sjogren, K. et al. Elevated aromatase expression in osteoblasts leads to increased bone mass without systemic adverse effects. J. Bone Min. Res. 24, 1263–1270 (2009). This preclinical study shows that osteoblasts overexpressing human aromatase induce a sclerotic response in mice, similar to the sclerotic response of CRPC.

    Article  Google Scholar 

  200. Fujimura, T., Takayama, K., Takahashi, S. & Inoue, S. Estrogen and androgen blockade for advanced prostate cancer in the era of precision medicine. Cancers 10, 29 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Scaglione, A. et al. Subcellular localization of the five members of the human steroid 5α-reductase family. Biochim. Open. 4, 99–106 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Deb, S. et al. Steroidogenesis in peripheral and transition zones of human prostate cancer tissue. Int. J. Mol. Sci. 22, 487 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Russell, D. W. & Wilson, J. D. Steroid 5α-reductase: two genes/two enzymes. Annu. Rev. Biochem. 63, 25–61 (1994).

    Article  CAS  PubMed  Google Scholar 

  204. Chavez, B., Ramos, L., Garcia-Becerra, R. & Vilchis, F. Hamster SRD5A3 lacks steroid 5α-reductase activity in vitro. Steroids 94, 41–50 (2015).

    Article  CAS  PubMed  Google Scholar 

  205. Uemura, M. et al. Novel 5α-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci. 99, 81–86 (2008).

    CAS  PubMed  Google Scholar 

  206. Cantagrel, V. et al. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142, 203–217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Stiles, A. R. & Russell, D. W. SRD5A3: a surprising role in glycosylation. Cell 142, 196–198 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Roehrborn, C. G. et al. Efficacy and safety of a dual inhibitor of 5-α-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 60, 434–441 (2002).

    Article  PubMed  Google Scholar 

  209. Bramson, H. N. et al. Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J. Pharmacol. Exp. Ther. 282, 1496–1502 (1997).

    CAS  PubMed  Google Scholar 

  210. Bartsch, G., Rittmaster, R. S. & Klocker, H. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. Eur. Urol. 37, 367–380 (2000).

    Article  CAS  PubMed  Google Scholar 

  211. Rittmaster, R., Hahn, R. G., Ray, P., Shannon, J. B. & Wurzel, R. Effect of dutasteride on intraprostatic androgen levels in men with benign prostatic hyperplasia or prostate cancer. Urology 72, 808–812 (2008).

    Article  PubMed  Google Scholar 

  212. Clark, R. V. et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J. Clin. Endocrinol. Metab. 89, 2179–2184 (2004).

    Article  CAS  PubMed  Google Scholar 

  213. Chang, K. H. et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 108, 13728–13733 (2011). This work is one of the studies providing evidence for the potential role of an alternative pathway for DHT synthesis in prostate cancer by bypassing the classical route where DHT is formed via testosterone as the precursor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Azuma, T., Matayoshi, Y., Sato, Y. & Nagase, Y. Effect of dutasteride on castration-resistant prostate cancer. Mol. Clin. Oncol. 8, 133–136 (2018).

    CAS  PubMed  Google Scholar 

  215. Mitsiades, N. et al. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res. 72, 6142–6152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Titus, M. A. et al. Steroid 5α-reductase isozymes I and II in recurrent prostate cancer. Clin. Cancer Res. 11, 4365–4371 (2005).

    Article  CAS  PubMed  Google Scholar 

  217. Penning, T. M. & Detlefsen, A. J. Intracrinology-revisited and prostate cancer. J. Steroid Biochem. Mol. Biol. 196, 105499 (2020).

    Article  CAS  PubMed  Google Scholar 

  218. McKay, R. R. et al. A phase II trial of abiraterone combined with dutasteride for men with metastatic castration-resistant prostate cancer. Clin. Cancer Res. 23, 935–945 (2017).

    Article  CAS  PubMed  Google Scholar 

  219. Thompson, I. M. et al. The influence of finasteride on the development of prostate cancer. N. Engl. J. Med. 349, 215–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  220. Andriole, G. L. et al. Effect of dutasteride on the risk of prostate cancer. N. Engl. J. Med. 362, 1192–1202 (2010).

    Article  CAS  PubMed  Google Scholar 

  221. Wallerstedt, A., Strom, P., Gronberg, H., Nordstrom, T. & Eklund, M. Risk of prostate cancer in men treated with 5α-reductase inhibitors—a large population-based prospective study. J. Natl Cancer Inst. 110, 1216–1221 (2018).

    Article  PubMed  Google Scholar 

  222. Unger, J. M. et al. Using Medicare claims to examine long-term prostate cancer risk of finasteride in the prostate cancer prevention trial. J. Natl Cancer Inst. 110, 1208–1215 (2018).

    PubMed  PubMed Central  Google Scholar 

  223. US National Library of Medicine. ClinicalTrials.gov. https://classic.clinicaltrials.gov/show/NCT02213107 (2014).

  224. von Wahlde, M. K. et al. The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/VEGF-signaling. Gynecol. Endocrinol. 31, 160–164 (2015).

    Article  Google Scholar 

  225. Karimaa, M. et al. First-in-class small molecule to inhibit CYP11A1 and steroid hormone biosynthesis. Mol. Cancer Ther. 21, 1765–1776 (2022). This paper describes the successful development of a CYP11A1 inhibitor now entering a phase II clinical study for prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  226. Fizazi, K. et al. Phase 1 results of the ODM-208 first-in-human phase 1–2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES). J. Clin. Oncol. 40 (Suppl. 6), 18 (2022).

    Article  Google Scholar 

  227. Brooke, G. N. & Bevan, C. L. The role of androgen receptor mutations in prostate cancer progression. Curr. Genom. 10, 18–25 (2009).

    Article  CAS  Google Scholar 

  228. Shi, X. B., Ma, A. H., Xia, L., Kung, H. J. & de Vere White, R. W. Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res. 62, 1496–1502 (2002).

    CAS  PubMed  Google Scholar 

  229. US National Library of Medicine. ClinicalTrials.gov. https://classic.clinicaltrials.gov/show/NCT03878823 (2019).

  230. Simard, J. et al. Molecular biology of the 3β-hydroxysteroid dehydrogenase/δ5-δ4 isomerase gene family. Endocr. Rev. 26, 525–582 (2005). This early review of the differences between expression and physiology of 3βHSD1 and 3βHSD2 enzymes provides the basis for the possibility of inhibiting peripheral 3βHSD activity without affecting steroid synthesis in the gonads and adrenal glands.

    Article  CAS  PubMed  Google Scholar 

  231. Thomas, J. L., Mason, J. I., Brandt, S., Spencer, B. R. Jr. & Norris, W. Structure/function relationships responsible for the kinetic differences between human type 1 and type 2 3β-hydroxysteroid dehydrogenase and for the catalysis of the type 1 activity. J. Biol. Chem. 277, 42795–42801 (2002).

    Article  CAS  PubMed  Google Scholar 

  232. Cui, D. et al. Cancer-associated fibroblast-secreted glucosamine alters the androgen biosynthesis program in prostate cancer via HSD3B1 upregulation. J. Clin. Invest. 133, e161913 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Chang, Y. C. et al. Expression of 3β-hydroxysteroid dehydrogenase type 1 in breast cancer is associated with poor prognosis independent of estrogen receptor status. Ann. Surg. Oncol. 24, 4033–4041 (2017).

    Article  PubMed  Google Scholar 

  234. Thomas, J. L. et al. Structure/function of the inhibition of human 3β-hydroxysteroid dehydrogenase type 1 and type 2 by trilostane. J. Steroid Biochem. Mol. Biol. 111, 66–73 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Zhuang, Q., Huang, S. & Li, Z. Prospective role of 3βHSD1 in prostate cancer precision medicine. Prostate 83, 619–627 (2023).

    Article  CAS  PubMed  Google Scholar 

  236. Agarwal, N. et al. Independent validation of effect of HSD3B1 genotype on response to androgen-deprivation therapy in prostate cancer. JAMA Oncol. 3, 856–857 (2017). This clinical study shows that a more stable variant of 3βHSD1 is associated with a poorer outcome for patients with prostate cancer during ADT, suggesting a key role for the enzyme in intracrine androgen synthesis.

    Article  PubMed  PubMed Central  Google Scholar 

  237. Hearn, J. W. D. et al. Association of HSD3B1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol. 4, 558–562 (2018).

    Article  PubMed  Google Scholar 

  238. Sabharwal, N. & Sharifi, N. HSD3B1 genotypes conferring adrenal-restrictive and adrenal-permissive phenotypes in prostate cancer and beyond. Endocrinology 160, 2180–2188 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Chang, K. H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Mei, Z. et al. Management of prostate cancer by targeting 3βHSD1 after enzalutamide and abiraterone treatment. Cell Rep. Med. 3, 100608 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Kruse, M. L. et al. Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer. JCI Insight 6, e150403 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  242. Flanagan, M. R. et al. Association of HSD3B1 genotype and clinical outcomes in postmenopausal estrogen-receptor-positive breast cancer. Ann. Surg. Oncol. 29, 7194–7201 (2022).

    Article  PubMed  Google Scholar 

  243. US National Library of Medicine. ClinicalTrials.gov. https://classic.clinicaltrials.gov/show/NCT05183828 (2022).

  244. Mueller, J. W., Gilligan, L. C., Idkowiak, J., Arlt, W. & Foster, P. A. The regulation of steroid action by sulfation and desulfation. Endocr. Rev. 36, 526–563 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Raftogianis, R., Creveling, C., Weinshilboum, R. & Weisz, J. Estrogen metabolism by conjugation. J. Natl Cancer Inst. Monogr. 2000, 113–124 (2000).

    Article  Google Scholar 

  246. Utsumi, T. et al. Elevated steroid sulfatase expression in breast cancers. J. Steroid Biochem. Mol. Biol. 73, 141–145 (2000).

    Article  CAS  PubMed  Google Scholar 

  247. Armstrong, C. M. et al. Steroid sulfatase stimulates intracrine androgen synthesis and is a therapeutic target for advanced prostate cancer. Clin. Cancer Res. 26, 6064–6074 (2020). This recent translational study describes the potential of steroid sulfatase as a target for inhibiting the formation of potent androgens, providing a treatment option for advanced prostate cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Pasqualini, J. R. et al. Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J. Clin. Endocrinol. Metab. 81, 1460–1464 (1996).

    CAS  PubMed  Google Scholar 

  249. Reed, M. J., Purohit, A., Woo, L. W., Newman, S. P. & Potter, B. V. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr. Rev. 26, 171–202 (2005).

    Article  CAS  PubMed  Google Scholar 

  250. Foster, P. A. et al. Efficacy of three potent steroid sulfatase inhibitors: pre-clinical investigations for their use in the treatment of hormone-dependent breast cancer. Breast Cancer Res. Treat. 111, 129–138 (2008).

    Article  CAS  PubMed  Google Scholar 

  251. Foster, P. A., Woo, L. W., Potter, B. V., Reed, M. J. & Purohit, A. The use of steroid sulfatase inhibitors as a novel therapeutic strategy against hormone-dependent endometrial cancer. Endocrinology 149, 4035–4042 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Stanway, S. J. et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin. Cancer Res. 12, 1585–1592 (2006).

    Article  CAS  PubMed  Google Scholar 

  253. Coombes, R. C. et al. A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res. Treat. 140, 73–82 (2013).

    Article  CAS  PubMed  Google Scholar 

  254. Foster, P. A. Steroid sulphatase and its inhibitors: past, present, and future. Molecules 26, 2852 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Palmieri, C. et al. IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer. Breast Cancer Res. Treat. 166, 527–539 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Palmieri, C. et al. IRIS study: a phase II study of the steroid sulfatase inhibitor irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients. Breast Cancer Res. Treat. 165, 343–353 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Saloniemi, T., Jokela, H., Strauss, L., Pakarinen, P. & Poutanen, M. The diversity of sex steroid action: novel functions of hydroxysteroid (17β)dehydrogenases as revealed by genetically modified mouse models. J. Endocrinol. 212, 27–40 (2012).

    Article  CAS  PubMed  Google Scholar 

  258. McNamara, K. M. & Sasano, H. The role of 17βHSDs in breast tissue and breast cancers. Mol. Cell Endocrinol. 489, 32–44 (2019).

    Article  CAS  PubMed  Google Scholar 

  259. Carruba, G. Estrogens and mechanisms of prostate cancer progression. Ann. N.Y. Acad. Sci. 1089, 201–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  260. Hiltunen, J. K. et al. 17β-Hydroxysteroid dehydrogenases as acyl thioester metabolizing enzymes. Mol. Cell Endocrinol. 489, 107–118 (2019).

    Article  CAS  PubMed  Google Scholar 

  261. Penning, T. M. AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): roles in malignancy and endocrine disorders. Mol. Cell Endocrinol. 489, 82–91 (2019).

    Article  CAS  PubMed  Google Scholar 

  262. Heinosalo, T., Saarinen, N. & Poutanen, M. Role of hydroxysteroid (17β)dehydrogenase type 1 in reproductive tissues and hormone-dependent diseases. Mol. Cell Endocrinol. 489, 9–31 (2019).

    Article  CAS  PubMed  Google Scholar 

  263. Lin, S. X. et al. Structural basis of the multispecificity demonstrated by 17β-hydroxysteroid dehydrogenase types 1 and 5. Mol. Cell Endocrinol. 248, 38–46 (2006).

    Article  CAS  PubMed  Google Scholar 

  264. Zhang, A., Zhang, J., Plymate, S. & Mostaghel, E. A. Classical and non-classical roles for pre-receptor control of DHT metabolism in prostate cancer progression. Horm. Cancer 7, 104–113 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Bauman, D. R., Steckelbroeck, S., Williams, M. V., Peehl, D. M. & Penning, T. M. Identification of the major oxidative 3α-hydroxysteroid dehydrogenase in human prostate that converts 5α-androstane-3α,17β-diol to 5α-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease. Mol. Endocrinol. 20, 444–458 (2006).

    Article  CAS  PubMed  Google Scholar 

  266. Paulukinas, R. D., Mesaros, C. A. & Penning, T. M. Conversion of classical and 11-oxygenated androgens by insulin-induced AKR1C3 in a model of human PCOS adipocytes. Endocrinology 163, bqac068 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Storbeck, K. H. A commentary on the origins of 11-ketotestosterone. Eur. J. Endocrinol. 187, C5–C8 (2022).

    Article  CAS  PubMed  Google Scholar 

  268. Rege, J. et al. 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. J. Clin. Endocrinol. Metab. 103, 4589–4598 (2018).

    PubMed  PubMed Central  Google Scholar 

  269. Rege, J. et al. Circulating 11-oxygenated androgens across species. J. Steroid Biochem. Mol. Biol. 190, 242–249 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Barnard, L. et al. 11-Oxygenated estrogens are a novel class of human estrogens but do not contribute to the circulating estrogen pool. Endocrinology 162, bqaa231 (2021).

    Article  PubMed  Google Scholar 

  271. Mostaghel, E. A. et al. Contribution of adrenal glands to intratumor androgens and growth of castration-resistant prostate cancer. Clin. Cancer Res. 25, 426–439 (2019).

    Article  CAS  PubMed  Google Scholar 

  272. Knuuttila, M. et al. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model. Am. J. Pathol. 184, 2163–2173 (2014).

    Article  CAS  PubMed  Google Scholar 

  273. Ishizaki, F. et al. Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer. Sci. Rep. 3, 1528 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  274. Mohler, J. L. et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 71, 1486–1496 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Hamid, A. R. et al. Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer. Mol. Med. 18, 1449–1455 (2013).

    Article  PubMed  Google Scholar 

  276. Fankhauser, M. et al. Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer. Clin. Cancer Res. 20, 5547–5557 (2014).

    Article  CAS  PubMed  Google Scholar 

  277. Penning, T. M., Asangani, I. A., Sprenger, C. & Plymate, S. Intracrine androgen biosynthesis and drug resistance. Cancer Drug. Resist. 3, 912–929 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Liu, C. et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res. 75, 1413–1422 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Liu, C. et al. Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. Mol. Cancer Ther. 16, 35–44 (2017).

    Article  CAS  PubMed  Google Scholar 

  280. Liedtke, A. J. et al. Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J. Med. Chem. 56, 2429–2446 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Penning, T. M. Aldo-keto reductase (AKR) 1C3 inhibitors: a patent review. Expert. Opin. Ther. Pat. 27, 1329–1340 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Kikuchi, A. et al. In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3). Invest. New Drugs 32, 860–870 (2014).

    Article  CAS  PubMed  Google Scholar 

  283. Loriot, Y. et al. Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study. Invest. New Drugs 32, 995–1004 (2014).

    Article  CAS  PubMed  Google Scholar 

  284. Chen, M. et al. Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. Bioorg. Med. Chem. Lett. 22, 3492–3497 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Abdelsamie, A. S. et al. Development of potential preclinical candidates with promising in vitro ADME profile for the inhibition of type 1 and type 2 17β-hydroxysteroid dehydrogenases: design, synthesis, and biological evaluation. Eur. J. Med. Chem. 178, 93–107 (2019).

    Article  CAS  PubMed  Google Scholar 

  286. Maltais, R. et al. Pharmacokinetic profile of PBRM in rodents, a first selective covalent inhibitor of 17β-HSD1 for breast cancer and endometriosis treatments. J. Steroid Biochem. Mol. Biol. 178, 167–176 (2018).

    Article  CAS  PubMed  Google Scholar 

  287. Messinger, J. et al. Estrone C15 derivatives—a new class of 17β-hydroxysteroid dehydrogenase type 1 inhibitors. Mol. Cell Endocrinol. 301, 216–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  288. Husen, B. et al. Human hydroxysteroid (17-β)dehydrogenase 1 expression enhances estrogen sensitivity of MCF-7 breast cancer cell xenografts. Endocrinology 147, 5333–5339 (2006).

    Article  CAS  PubMed  Google Scholar 

  289. US National Library of Medicine. ClinicalTrials.gov. https://classic.clinicaltrials.gov/show/NCT05560646 (2022).

  290. Hilborn, E., Stal, O. & Jansson, A. Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer. Oncotarget 8, 30552–30562 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  291. Poutanen, M., Isomaa, V., Lehto, V. P. & Vihko, R. Immunological analysis of 17β-hydroxysteroid dehydrogenase in benign and malignant human breast tissue. Int. J. Cancer 50, 386–390 (1992).

    Article  CAS  PubMed  Google Scholar 

  292. Hanamura, T. et al. Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers. Breast Cancer Res. Treat. 143, 69–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  293. Knuuttila, M., Hamalainen, E. & Poutanen, M. Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer. J. Mol. Endocrinol. 62, R255–R267 (2019). This recent review describes the utilization of highly sensitive mass-spectrometric analyses to measure sex steroid concentrations in bodily fluids and tissues.

    Article  CAS  PubMed  Google Scholar 

  294. Takagi, M. et al. Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas. Breast Cancer Res. Treat. 156, 45–55 (2016).

    Article  CAS  PubMed  Google Scholar 

  295. Bremmer, F. et al. Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer. Oncotarget 9, 16951–16961 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  296. Muthusamy, S. et al. Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer. Proc. Natl Acad. Sci. USA 108, 20090–20094 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Li, Z. et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015). This paper presents an example of the ability of a steroid metabolic enzyme to act in drug metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Li, Z. et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533, 547–551 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Alyamani, M. et al. Steroidogenic metabolism of galeterone reveals a diversity of biochemical activities. Cell Chem. Biol. 24, 825–832.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Plosker, G. L. & Brogden, R. N. Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders. Drugs 48, 930–967 (1994).

    Article  CAS  PubMed  Google Scholar 

  301. Kurebayashi, J. et al. A follow-up study of a randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-month depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer. Breast Cancer 28, 684–697 (2021).

    Article  PubMed  Google Scholar 

  302. Kendzierski, D. C., Schneider, B. P. & Kiel, P. J. Efficacy of different leuprolide administration schedules in premenopausal breast cancer: a retrospective review. Clin. Breast Cancer 18, e939–e942 (2018).

    Article  CAS  PubMed  Google Scholar 

  303. Tyrrell, C. J. et al. Comparison of an LH-RH analogue (goeserelin acetate, ‘Zoladex’) with combined androgen blockade in advanced prostate cancer: final survival results of an international multicentre randomized-trial. International Prostate Cancer Study Group. Eur. Urol. 37, 205–211 (2000).

    Article  CAS  PubMed  Google Scholar 

  304. Lundstrom, E. A. et al. Triptorelin 6-month formulation in the management of patients with locally advanced and metastatic prostate cancer: an open-label, non-comparative, multicentre, phase III study. Clin. Drug. Investig. 29, 757–765 (2009).

    Article  CAS  PubMed  Google Scholar 

  305. Lahlou, N. [Pharmacokinetics and pharmacodynamics of triptorelin]. Ann. Urol. 39, S78–S84 (2005).

    Article  Google Scholar 

  306. Broqua, P. et al. Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix. J. Pharmacol. Exp. Ther. 301, 95–102 (2002).

    Article  CAS  PubMed  Google Scholar 

  307. Shore, N. D. et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N. Engl. J. Med. 382, 2187–2196 (2020).

    Article  CAS  PubMed  Google Scholar 

  308. Mouridsen, H. et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the international letrozole breast cancer group. J. Clin. Oncol. 21, 2101–2109 (2003). This study reports marked efficacy of letrozole, one of the third-generation aromatase inhibitors, in increasing overall survival of postmenopausal women with locally advanced or metastatic ER+ breast cancer compared with tamoxifen.

    Article  CAS  PubMed  Google Scholar 

  309. DeMichele, A. et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2– metastatic breast cancer in US real-world clinical practice. Breast Cancer Res. 23, 37 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. O’Shaughnessy, J. et al. Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2– advanced breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res. Treat. 168, 127–134 (2018).

    Article  PubMed  Google Scholar 

  311. Hortobagyi, G. N. et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N. Engl. J. Med. 386, 942–950 (2022). This study represents an example of combination treatment of an aromatase inhibitor with a CDK4/6 inhibitor increasing the efficacy of an aromatase inhibitor alone in advanced ER+ breast cancer.

    Article  CAS  PubMed  Google Scholar 

  312. Shah, A. et al. FDA approval: ribociclib for the treatment of postmenopausal women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Clin. Cancer Res. 24, 2999–3004 (2018).

    Article  CAS  PubMed  Google Scholar 

  313. Bonneterre, J. et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92, 2247–2258 (2001).

    Article  CAS  PubMed  Google Scholar 

  314. Hurvitz, S. A. et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR+/HER2– breast cancer. Clin. Cancer Res. 26, 566–580 (2020).

    Article  CAS  PubMed  Google Scholar 

  315. Kaufmann, M. et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J. Clin. Oncol. 18, 1399–1411 (2000).

    Article  CAS  PubMed  Google Scholar 

  316. Raphael, J. et al. Everolimus in advanced breast cancer: a systematic review and meta-analysis. Target. Oncol. 15, 723–732 (2020).

    Article  PubMed  Google Scholar 

  317. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/study/NCT02580448 (2015).

  318. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/study/NCT02935205 (2017).

  319. US National Library of Medicine. ClinicalTrials.gov. https://www.clinicaltrials.gov/study/NCT04677855 (2022).

  320. Weigel, N. L. & Zhang, Y. Ligand-independent activation of steroid hormone receptors. J. Mol. Med. 76, 469–479 (1998).

    Article  CAS  PubMed  Google Scholar 

  321. Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 13, 1141–1151 (2012).

    Article  PubMed Central  Google Scholar 

  322. Li, C. et al. Parity and risk of developing breast cancer according to tumor subtype: a systematic review and meta-analysis. Cancer Epidemiol. 75, 102050 (2021).

    Article  PubMed  Google Scholar 

  323. Morch, L. S. et al. Contemporary hormonal contraception and the risk of breast cancer. N. Engl. J. Med. 377, 2228–2239 (2017).

    Article  PubMed  Google Scholar 

  324. Santen, R. J. et al. Underlying breast cancer risk and menopausal hormone therapy. J. Clin. Endocrinol. Metab. 105, dgaa073 (2020).

    Article  PubMed  Google Scholar 

  325. Morgentaler, A. Testosterone and prostate cancer: what are the risks for middle-aged men? Urol. Clin. North. Am. 38, 119–124 (2011).

    Article  PubMed  Google Scholar 

  326. Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  328. Sathianathen, N. J. et al. Indirect comparisons of efficacy between combination approaches in metastatic hormone-sensitive prostate cancer: a systematic review and network meta-analysis. Eur. Urol. 77, 365–372 (2020).

    Article  CAS  PubMed  Google Scholar 

  329. Saad, F. et al. Emerging therapeutic targets for patients with advanced prostate cancer. Cancer Treat. Rev. 76, 1–9 (2019).

    Article  CAS  PubMed  Google Scholar 

  330. Burstein, H. J. et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J. Clin. Oncol. 39, 3959–3977 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  331. Chen, J. et al. Comparison of current systemic combination therapies for metastatic hormone-sensitive prostate cancer and selection of candidates for optimal treatment: a systematic review and bayesian network meta-analysis. Front. Oncol. 10, 519388 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  332. Saatci, O., Huynh-Dam, K. T. & Sahin, O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J. Mol. Med. 99, 1691–1710 (2021).

    Article  CAS  PubMed  Google Scholar 

  333. Nagarajan, S. et al. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat. Genet. 52, 187–197 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  334. Zhang, Z. et al. Loss of CHD1 promotes heterogeneous mechanisms of resistance to AR-targeted therapy via chromatin dysregulation. Cancer Cell 37, 584–598.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  335. Colleoni, M. et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the International Breast Cancer Study Group trials I to V. J. Clin. Oncol. 34, 927–935 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. Pound, C. R. et al. Natural history of progression after PSA elevation following radical prostatectomy. J. Am. Med. Assoc. 281, 1591–1597 (1999).

    Article  CAS  Google Scholar 

  337. Coleman, R. E. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat. Rev. 27, 165–176 (2001). This work is one of the first reviews describing the clinical features of bone metastasis.

    Article  CAS  PubMed  Google Scholar 

  338. Clezardin, P. et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol. Rev. 101, 797–855 (2021).

    Article  CAS  PubMed  Google Scholar 

  339. Coleman, R. E. Skeletal complications of malignancy. Cancer 80, 1588–1594 (1997).

    Article  CAS  PubMed  Google Scholar 

  340. Riggs, B. L., Khosla, S. & Melton, L. J. 3rd Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 23, 279–302 (2002). This review describes the concept of sex hormones and the regulation of bone mass.

    Article  CAS  PubMed  Google Scholar 

  341. Vanderschueren, D. et al. Androgens and bone. Endocr. Rev. 25, 389–425 (2004).

    Article  CAS  PubMed  Google Scholar 

  342. Vaananen, H. K. & Harkonen, P. L. Estrogen and bone metabolism. Maturitas 23, S65–S69 (1996).

    Article  CAS  PubMed  Google Scholar 

  343. Ishida, Y. et al. Expression of steroid-converting enzymes in osteoblasts derived from rat vertebrae. Osteoporos. Int. 13, 235–240 (2002).

    Article  CAS  PubMed  Google Scholar 

  344. Nawata, H. et al. Aromatase in bone cell: association with osteoporosis in postmenopausal women. J. Steroid Biochem. Mol. Biol. 53, 165–174 (1995).

    Article  CAS  PubMed  Google Scholar 

  345. Liu, L., Pathak, J. L., Zhu, Y. Q. & Bureik, M. Comparison of cytochrome P450 expression in four different human osteoblast models. Biol. Chem. 398, 1327–1334 (2017).

    Article  CAS  PubMed  Google Scholar 

  346. Kasperk, C. et al. Skeletal site-dependent expression of the androgen receptor in human osteoblastic cell populations. Calcif. Tissue Int. 61, 464–473 (1997).

    Article  CAS  PubMed  Google Scholar 

  347. Arts, J. et al. Differential expression of estrogen receptors α and β mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology 138, 5067–5070 (1997).

    Article  CAS  PubMed  Google Scholar 

  348. Issa, S. et al. Human osteoblast-like cells express predominantly steroid 5α-reductase type 1. J. Clin. Endocrinol. Metab. 87, 5401–5407 (2002).

    Article  CAS  PubMed  Google Scholar 

  349. Gondo, S. et al. Adipose tissue-derived and bone marrow-derived mesenchymal cells develop into different lineage of steroidogenic cells by forced expression of steroidogenic factor 1. Endocrinology 149, 4717–4725 (2008).

    Article  CAS  PubMed  Google Scholar 

  350. Rubinow, K. B. An intracrine view of sex steroids, immunity, and metabolic regulation. Mol. Metab. 15, 92–103 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  351. Robert, F. et al. Synthesis of progesterone in Schwann cells: regulation by sensory neurons. Eur. J. Neurosci. 13, 916–924 (2001).

    Article  CAS  PubMed  Google Scholar 

  352. Schumacher, M. et al. Progesterone synthesis and myelin formation in peripheral nerves. Brain Res. Brain Res. Rev. 37, 343–359 (2001).

    Article  CAS  PubMed  Google Scholar 

  353. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013). This important early study shows that CYP17A1 inhibition improves the outcome of patients with metastatic CRPC.

    Article  CAS  PubMed  Google Scholar 

  354. Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  355. Blair, J. M., Zhou, H., Seibel, M. J. & Dunstan, C. R. Mechanisms of disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat. Clin. Pract. Oncol. 3, 41–49 (2006).

    Article  CAS  PubMed  Google Scholar 

  356. Lee, Y. et al. Differences in the cytokine profiles associated with prostate cancer cell induced osteoblastic and osteolytic lesions in bone. J. Orthop. Res. 21, 62–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  357. Guise, T. A. The vicious cycle of bone metastases. J. Musculoskelet. Neuronal Interact. 2, 570–572 (2002).

    CAS  PubMed  Google Scholar 

  358. Roodman, G. D. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004). This work is one of the first reviews describing how tumour cells cause bone metastases by producing both local and systemic factors that disrupt the balance between bone formation and bone resorption.

    Article  CAS  PubMed  Google Scholar 

  359. Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011). This work is a more recent review of the current knowledge of bone metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland

    Matti Poutanen & Pirkko Härkönen

  2. Turku Center for Disease Modelling, University of Turku, Turku, Finland

    Matti Poutanen

  3. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

    Matti Poutanen & Malin Hagberg Thulin

  4. FICAN West Cancer Center, University of Turku and Turku University Hospital, Turku, Finland

    Matti Poutanen & Pirkko Härkönen

Authors
  1. Matti Poutanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malin Hagberg Thulin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pirkko Härkönen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, contributed substantially to discussion of the content, and wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Matti Poutanen.

Ethics declarations

Competing interests

M.P. receives funding and research support from Orion Pharma and Forendo Pharma, has a consultation agreement with Forendo Pharma (past) and Organon & Co (current), and co-supervises a Ph.D. student at Orion Pharma. M.H.T and P.H. declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Stephen Plymate and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

The International Genome Sample Resource (IGSR): https://www.internationalgenome.org/data

Glossary

Adrenal cortex

The outer part of the adrenal gland including cells synthesizing steroids, such as mineralocorticoids, glucocorticoids and sex steroid precursors.

Adrenal insufficiency

A condition in which the adrenal cortex fails to produce adequate amounts of steroid hormones for physiological requirements.

Aldosterone

A steroid hormone produced in the adrenal cortex regulating water and salt balance.

Apocrine-type AR-positive breast cancer

A rare subtype of oestrogen receptor (ER)-negative, androgen receptor (AR)-expressing (AR+) breast cancer.

Arthralgias

Pain in joints or joint stiffness.

Cortisol

A steroid hormone synthesized in the adrenal cortex with wide biological actions regulating, for example, metabolism, blood pressure and immune functions.

Endometriosis

A disease causing pain and infertility in which endometrial mucosa (glands and stroma) grow in ectopic locations outside the uterine cavity.

Epimerase

An enzyme that catalyses the inversion between two stereoisomers of a chemical compound, such as a steroid. Stereoisomers are molecules that have the same molecular formula and sequence of bonded atoms, but the atoms differ in their three-dimensional orientations.

Follicle-stimulating hormone

(FSH). A peptide hormone secreted from the anterior lobe of the pituitary gland that supports ovarian steroid hormone synthesis and growth of the follicles.

Glucocorticoid receptors

Members of the nuclear receptor family that mediates the actions of glucocorticoids, such as cortisol and corticosterone, by activating or repressing target genes.

Gonadotrophs

A specialized cell type of the anterior pituitary that synthesizes and secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Intracrine sex steroid synthesis

Synthesis of the active steroid hormone in the target cells.

Luteinizing hormone

(LH). A peptide hormone secreted from the anterior lobe of the pituitary gland that supports ovarian steroid hormone synthesis and induces ovulation, and also stimulates testosterone production in the testis in men.

Mineralocorticoid receptors

Members of the nuclear receptor family which mediate the actions of mineralocorticoids, such as aldosterone by activating or repressing target genes.

Oophorectomy

Surgical removal of the ovaries.

Perimenopausal

The time around menopause when the formation of ovarian follicles gradually ceases and fertility decreases.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Poutanen, M., Hagberg Thulin, M. & Härkönen, P. Targeting sex steroid biosynthesis for breast and prostate cancer therapy. Nat Rev Cancer 23, 686–709 (2023). https://doi.org/10.1038/s41568-023-00609-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-023-00609-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer