Skip to main content

Advertisement

SpringerLink
Log in

A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Endocrine therapy is the ideal treatment choice for estrogen receptor α (ERα)-positive breast cancer patients. Principal used therapies target either the ERα e.g. by selective ERα modulators (SERMs) such as tamoxifen or target estrogen biosynthesis with aromatase inhibitors. Steroid sulfatase (STS) plays a crucial role in formation of compounds with estrogenic properties, converting inactive sulfate-conjugated steroids to active non-conjugated forms. Steroid sulfates are considered as a reservoir for active steroids due to their prolonged half-life and increased concentration in plasma. STS is present in several tissues including the breast, and the STS the mRNA level and enzyme activity is significantly increased in ERα-positive breast tumors. Inhibition of STS is therefore a new approach for decreasing estrogenic steroids that stimulate breast cancer. The novel dual-acting compound SR 16157 is designed as a sulfamate-containing STS inhibitor that releases a tissue-selective SERM SR 16137. Use of a dual-target STS inhibitor and SERM represents a new strategy in the treatment of hormone-dependent breast cancer. In this study, we tested the potential of SR 16157 and SR 16137 on STS activity, cell growth and ERα function in MCF-7 breast cancer cells. We confirmed that the dual-target compound SR 16157 exerts STS inhibition and antiestrogenic effects. SR 16157 was a highly effective growth inhibitor, being 10 times more potent than the antiestrogens SR 16137 and tamoxifen. Relative to tamoxifen, SR 16137 displays profoundly improved ERα binding affinity and antiestrogenic effects on expression of estrogen-regulated genes. Thus, the dual-target SR 16157 is possibly a promising new treatment alternative, superior to tamoxifen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Suzuki T, Moriya T, Ishida T et al (2003a) Intracrine mechanism of estrogen synthesis in breast cancer. Biomed Pharmacother 57(10):460–462

    Article  CAS  Google Scholar 

  2. Thijssen JH (2004) Local biosynthesis and metabolism of oestrogens in the human breast. Maturitas 49(1):25–33

    Article  PubMed  CAS  Google Scholar 

  3. Buzdar AU (2001) Endocrine therapy in the treatment of metastatic breast cancer. Semin Oncol 28(3):291–304

    Article  PubMed  CAS  Google Scholar 

  4. Nicholson RI, Johnston SR (2005) Endocrine therapy-current benefits and limitations. Breast Cancer Res Treat 93(Suppl 1):S3–S10

    Article  PubMed  CAS  Google Scholar 

  5. Howell SJ, Johnston SR, Howell A (2004) The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer. Best Pract Res Clin Endocrinol Metab 18(1):47–66

    Article  PubMed  CAS  Google Scholar 

  6. Reed MJ, Purohit A, Woo LW et al (2005) Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev 26(2):171–202

    Article  PubMed  CAS  Google Scholar 

  7. Chetrite GS, Cortes-Prieto J, Philippe JC et al (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72(1–2):23–27

    Article  PubMed  CAS  Google Scholar 

  8. Pasqualini JR, Chetrite G, Blacker C et al (1996) 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(4):1460–1464

    Article  PubMed  CAS  Google Scholar 

  9. Santner SJ, Feil PD, Santen RJ (1984) In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. J Clin Endocrinol Metab 59(1):29–33

    Article  PubMed  CAS  Google Scholar 

  10. Ruder HJ, Loriaux L, Lipsett MB (1972) Estrone sulfate: production rate and metabolism in man. J Clin Invest 51(4):1020–1033

    Article  PubMed  CAS  Google Scholar 

  11. Pasqualini JR, Gelly C, Nguyen BL et al (1989) Importance of estrogen sulfates in breast cancer. J Steroid Biochem 34(1–6):155–163

    Article  PubMed  CAS  Google Scholar 

  12. Pasqualini JR, Chetrite GS (2005) Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol 93(2–5):221–236

    Article  PubMed  CAS  Google Scholar 

  13. Labrie F, Luu-The V, Belanger A et al (2005) Is dehydroepiandrosterone a hormone? J Endocrinol 187(2):169–196

    Article  PubMed  CAS  Google Scholar 

  14. Simpson ER (2003) Sources of estrogen and their importance. J Steroid Biochem Mol Biol 86(3–5):225–230

    Article  PubMed  CAS  Google Scholar 

  15. Maggiolini M, Donze O, Jeannin E et al (1999) Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor alpha. Cancer Res 59(19):4864–4869

    PubMed  CAS  Google Scholar 

  16. Billich A, Nussbaumer P, Lehr P (2000) Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors. J Steroid Biochem Mol Biol 73(5):225–235

    Article  PubMed  CAS  Google Scholar 

  17. Utsumi T, Yoshimura N, Takeuchi S et al (2000) Elevated steroid sulfatase expression in breast cancers. J Steroid Biochem Mol Biol 73(3–4):141–145

    Article  PubMed  CAS  Google Scholar 

  18. Miyoshi Y, Ando A, Hasegawa S et al (2003) High expression of steroid sulfatase mRNA predicts poor prognosis in patients with estrogen receptor-positive breast cancer. Clin Cancer Res 9(6):2288–2293

    PubMed  CAS  Google Scholar 

  19. Suzuki T, Nakata T, Miki Y et al (2003b) Estrogen sulfotransferase and steroid sulfatase in human breast carcinoma. Cancer Res 63(11):2762–2770

    CAS  Google Scholar 

  20. Carlstrom K, Doberl A, Gershagen S et al (1984a) Peripheral levels of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and testosterone following different doses of danazol. Acta Obstet Gynecol Scand Suppl 123:125–129

    CAS  Google Scholar 

  21. Carlstrom K, Doberl A, Pousette A et al (1984b) Inhibition of steroid sulfatase activity by danazol. Acta Obstet Gynecol Scand Suppl 123:107–111

    Article  CAS  Google Scholar 

  22. Purohit A, Williams GJ, Howarth NM et al (1995) Inactivation of steroid sulfatase by an active site-directed inhibitor, estrone-3-O-sulfamate. Biochemistry 34(36):11508–11514

    Article  PubMed  CAS  Google Scholar 

  23. Elger W, Schwarz S, Hedden A et al (1995) Sulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral application. J Steroid Biochem Mol Biol 55(3–4):395–403

    Article  PubMed  CAS  Google Scholar 

  24. Purohit A, Woo LW, Potter BV et al (2000) In vivo inhibition of estrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATE. Cancer Res 60(13):3394–3396

    PubMed  CAS  Google Scholar 

  25. Stanway JS, Purohit A, Woo LW et al (2006) Phase I Study of STX 64 (667 coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin Cancer Res 12(5):1585–1592

    Article  PubMed  CAS  Google Scholar 

  26. Fotsis T, Zhang Y, Pepper MS, Adlercreutz MS, Montesano R, Nawroth PP et al (1994) The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368(6468):237–239

    Article  PubMed  CAS  Google Scholar 

  27. Ciobanu LC, Luu-The V, Martel C et al (2003) Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase. Cancer Res 63(19):6442–6446

    PubMed  CAS  Google Scholar 

  28. Raobaikady B, Purohit A, Chander SK et al (2003) Inhibition of MCF-7 breast cancer cell proliferation and in vivo steroid sulphatase activity by 2-methoxyoestradiol-bis-sulphamate. J Steroid Biochem Mol Biol 84(2–3):351–358

    Article  PubMed  CAS  Google Scholar 

  29. MacCarthy-Morrogh L, Townsend PA, Purohit A et al (2000) Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest, apoptosis, and microtubule assembly in human breast cancer cells. Cancer Res 60(19):5441–5450

    PubMed  CAS  Google Scholar 

  30. Chu GH, Peters A, Selcer KW et al (1999) Synthesis and sulfatase inhibitory activities of (E)- and (Z)-4-hydroxytamoxifen sulfamates. Bioorg Med Chem Lett 9(2):141–144

    Article  PubMed  CAS  Google Scholar 

  31. Walter G, Liebl R, von Angerer E (2004) Stilbene-based inhibitors of estrone sulfatase with a dual mode of action in human breast cancer cells. Arch Pharm (Weinheim) 337(12):634–644

    Article  CAS  Google Scholar 

  32. Briand P, Lykkesfeldt AE (1984) Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to growth at low serum concentration. Cancer Res 44(3):1114–1119

    PubMed  CAS  Google Scholar 

  33. Lykkesfeldt AE, Briand P (1986) Indirect mechanism of oestradiol stimulation of cell proliferation of human breast cancer cell lines. Br J Cancer 53(1):29–35

    PubMed  CAS  Google Scholar 

  34. Lykkesfeldt AE, Madsen MW, Briand P (1994) Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res 54(6):1587–1595

    PubMed  CAS  Google Scholar 

  35. Lykkesfeldt AE, Larsen SS, Briand P (1995) Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer 61(4):529–534

    Article  PubMed  CAS  Google Scholar 

  36. Lykkesfeldt G, Lykkesfeldt AE, Skakkebaek NE (1984) Steroid sulphatase in man: a non inactivated X-locus with partial gene dosage compensation. Hum Genet 65(4):355–357

    Article  PubMed  CAS  Google Scholar 

  37. Lundholt BK, Briand P, Lykkesfeldt AE (2001) Growth inhibition and growth stimulation by estradiol of estrogen receptor transfected human breast epithelial cell lines involve different pathways. Breast Cancer Res Treat 67(3):199–214

    Article  PubMed  CAS  Google Scholar 

  38. Edwards DP, Martin PM, Horwitz KB et al (1980) Subcellular compartmentalization of estrogen receptors in human breast cancer cells. Exp Cell Res 127(1):197–213

    Article  PubMed  CAS  Google Scholar 

  39. Nawaz Z, Lonard DM, Dennis AP et al (1999) Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci USA 96(5):1858–1862

    Article  PubMed  CAS  Google Scholar 

  40. El Khissiin A, Journe F, Laios I et al (2000) Evidence of an estrogen receptor form devoid of estrogen binding ability in MCF-7 cells. Steroids 65(12):903–913

    Article  PubMed  CAS  Google Scholar 

  41. Marsaud V, Gougelet A, Maillard S et al (2003) Various phosphorylation pathways, depending on agonist and antagonist binding to endogenous estrogen receptor alpha (ERalpha), differentially affect ERalpha extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. Mol Endocrinol 17(10):2013–2027

    Article  PubMed  CAS  Google Scholar 

  42. Brown AM, Jeltsch JM, Roberts M et al (1984) Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7. Proc Natl Acad Sci USA 81(20):6344–6348

    Article  PubMed  CAS  Google Scholar 

  43. Kastner P, Krust A, Turcotte B et al (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9(5):1603–1614

    PubMed  CAS  Google Scholar 

  44. Steward AJ, Johnsen MD, May FEB, Westley BR (1990) Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem 265(34):21172–21178

    Google Scholar 

  45. Rochefort H, Chalbos D, Cunat S et al (2001) Estrogen regulated proteases and antiproteases in ovarian and breast cancer cells. J Steroid Biochem Mol Biol 76(1–5):119–124

    Article  PubMed  CAS  Google Scholar 

  46. Liaudet-Coopman E, Beaujouin M, Derocq D et al (2005) Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett 18:167–179

    Google Scholar 

  47. Gompel A, Chaouat M, Hugol D et al (2004) Steroidal hormones and proliferation, differentiation and apoptosis in breast cells. Maturitas 49(1):16–24

    Article  PubMed  CAS  Google Scholar 

  48. de Cremoux P, Tran-Perennou C, Brockdorff BL et al (2003) Validation of real-time RT-PCR for analysis of human breast cancer cell lines resistant or sensitive to treatment with antiestrogens. Endocr Relat Cancer 10(3):409–418

    Article  PubMed  Google Scholar 

  49. Christensen GL, Jepsen JS, Fog CK et al (2004) Sequential versus combined treatment of human breast cancer cells with antiestrogens and the vitamin D analogue EB1089 and evaluation of predictive markers for vitamin D treatment. Breast Cancer Res Treat 85(1):53–63

    Article  PubMed  CAS  Google Scholar 

  50. Larsen SS, Madsen MW, Jensen B et al (1997) Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness. Int J Cancer 72(6):1129–1136

    Article  PubMed  CAS  Google Scholar 

  51. Horwitz KB, Zava DT, Thilagar AK et al (1978) Steroid receptor analyses of nine human beast cancer cell lines. Cancer Res 38:4327–4339

    Google Scholar 

  52. Elger W, Palme HJ, Schwarz S (1998) Novel oestrogen sulfamates: a new approach to oral hormone therapy. Expert Opin Investig Drugs 7(4):575–589

    Article  PubMed  CAS  Google Scholar 

  53. Surmacz E (2000) Function of the IGF-I receptor in breast cancer. J Mammary Gland Biol Neoplasia 5(1):95–105

    Article  PubMed  CAS  Google Scholar 

  54. Brouillet JP, Dufour F, Lemamy G et al (1997) Increased cathepsin D level in the serum of patients with metastatic breast carcinoma detected with a specific pro-cathepsin D immunoassay. Cancer 79(11):2132–2136

    Article  PubMed  CAS  Google Scholar 

  55. Glondu M, Liaudet-Coopman E, Derocq D et al (2002) Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells. Oncogene 21(33):5127–5134

    Article  PubMed  CAS  Google Scholar 

  56. Sepp-Lorenzino L (1998) Structure and function of the insulin-like growth factor I receptor. Breast Cancer Res Treat 47(3):235–253

    Article  PubMed  CAS  Google Scholar 

  57. Zaveri NT, Chao W-R, Peters RH, Tanabe M, Yamada Y, Toko T, Asao T, Eshima K (2003) A novel dual-targeted approach for the endocrine therapy and prevention of breast cancer: SR 16158, a novel steroid sulfatase inhibitor/tissue-selective antiestrogen SERM. AACR advances in breast cancer research conference proceedings, Abstract B25, October 8–12, 2003, Huntington Beach, CA

  58. Fuqua S, Schiff R, Parra I et al (1999) Expression of wild-type estrogen receptor β and variant isoforms in human breast cancer. Cancer Res 59:5425–5428

    PubMed  CAS  Google Scholar 

  59. Winum JY, Vullo D, Casini A et al (2003) Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane, tumor-associated isozyme IX with sulfamates including EMATE also acting as steroid sulfatase inhibitors. J Med Chem 46(11):2197–2204

    Article  PubMed  CAS  Google Scholar 

  60. Winum JY, Scozzafava A, Montero JL et al (2005) Sulfamates and their therapeutic potential. Med Res Rev 25(2):186–228

    Article  PubMed  CAS  Google Scholar 

  61. Ho YT, Purohit A, Vicker N et al 2003) Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates. Biochem Biophys Res Commun 305(4):909–914

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Inger Heiberg and Birgit Reiter for excellent technical assistance. This work was supported by grants from the Danish Cancer Society’s Scientific Committee (DNLU).

Author information

Authors and Affiliations

  1. Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Louise M. Rasmussen, Jan Stenvang & Anne E. Lykkesfeldt

  2. Biosciences Division, SRI International, Menlo Park, CA, 94025, USA

    Nurulain T. Zaveri & Richard H. Peters

Authors
  1. Louise M. Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nurulain T. Zaveri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Stenvang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard H. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne E. Lykkesfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne E. Lykkesfeldt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rasmussen, L.M., Zaveri, N.T., Stenvang, J. et al. A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer. Breast Cancer Res Treat 106, 191–203 (2007). https://doi.org/10.1007/s10549-007-9494-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-007-9494-y

Keywords

Search

Navigation