Abstract
Estrogen plays crucial roles in the progression of hormone-dependent breast cancers through activation of nuclear estrogen receptor α (ER). Estrogen is produced locally from circulating inactive steroids and adrenal androgens in postmenopausal women. However, conversion by aromatase is a rate-limiting step in intratumoral estrogen production in breast cancer. Aromatase inhibitors (AIs) inhibit the growth of hormone-dependent breast cancers by blocking the conversion of adrenal androgens to estrogen and by unmasking the inhibitory effect of androgens, acting via the androgen receptor (AR). AIs are thus a standard treatment option for postmenopausal hormone-dependent breast cancer. However, although initial use of AIs provides substantial clinical benefit, some breast cancer patients relapse because of the acquisition of AI resistance. A better understanding of the mechanisms of AI resistance may contribute to the development of new therapeutic strategies and aid in the search for new therapeutic targets and agents. We have investigated AI-resistance mechanisms and established six AI-resistant cell lines. Some of them exhibit estrogen depletion-resistance properties via constitutive ER-activation or ER-independent growth signaling. We examined how breast cancer cells can adapt to estrogen depletion and androgen superabundance. Estrogen and estrogenic androgen produced independently from aromatase contributed to cell proliferation in some of these cell lines, while another showed AR-dependent cell proliferation. Based on these findings, currently proposed AI-resistance mechanisms include an aromatase-independent estrogen-producing pathway, estrogen-independent ER function, and ER-independent growth signaling. This review summarizes several hypotheses of AI-resistance mechanisms and discusses how existing or novel therapeutic agents may be applied to treat AI-resistant breast cancers.
Similar content being viewed by others
References
Clarke R, Leonessa F, Welch JN, Skaar TC. Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev. 2001;53:25–71.
Yamashita H. Current research topics in endocrine therapy for breast cancer. Int J Clin Oncol. 2008;13:380–3.
Miller WR, Larionov AA. Understanding the mechanisms of aromatase inhibitor resistance. Breast Cancer Res. 2012;14:201.
Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005;23:619–29.
Chlebowski R, Cuzick J, Amakye D, Bauerfeind I, Buzdar A, Chia S, et al. Clinical perspectives on the utility of aromatase inhibitors for the adjuvant treatment of breast cancer. Breast. 2009;18(Suppl 2):S1–11.
Chumsri S, Howes T, Bao T, Sabnis G, Brodie A. Aromatase, aromatase inhibitors, and breast cancer. J Steroid Biochem Mol Biol. 2011;125:13–22.
Lao Romera J, Puertolas Hernandez TJ, Pelaez Fernandez I, Sampedro Gimeno T, Fernandez Martinez R, Fernandez Perez I, et al. Update on adjuvant hormonal treatment of early breast cancer. Adv Ther. 2011;28(Suppl 6):1–18.
Miller WR, Anderson TJ, Jack WJ. Relationship between tumour aromatase activity, tumour characteristics and response to therapy. J Steroid Biochem Mol Biol. 1990;37:1055–9.
Hayashi S, Niwa T, Yamaguchi Y. Estrogen signaling pathway and its imaging in human breast cancer. Cancer Sci. 2009;100:1773–8.
Sasano H, Miki Y, Nagasaki S, Suzuki T. In situ estrogen production and its regulation in human breast carcinoma: from endocrinology to intracrinology. Pathol Int. 2009;59:777–89.
Subramanian A, Salhab M, Mokbel K. Oestrogen producing enzymes and mammary carcinogenesis: a review. Breast Cancer Res Treat. 2008;111:191–202.
Geisler J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol. 2003;86:245–53.
Miller WR. Aromatase and the breast: regulation and clinical aspects. Maturitas. 2006;54:335–41.
Ando S, De Amicis F, Rago V, Carpino A, Maggiolini M, Panno ML, et al. Breast cancer: from estrogen to androgen receptor. Mol Cell Endocrinol. 2002;193:121–8.
Castellano I, Allia E, Accortanzo V, Vandone AM, Chiusa L, Arisio R, et al. Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res Treat. 2010;124:607–17.
Choi J, Psarommatis B, Gao YR, Zheng Y, Handelsman DJ, Simanainen U. The role of androgens in experimental rodent mammary carcinogenesis. Breast Cancer Res. 2014;16:483.
Macedo LF, Guo Z, Tilghman SL, Sabnis GJ, Qiu Y, Brodie A. Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res. 2006;66:7775–82.
Panet-Raymond V, Gottlieb B, Beitel LK, Pinsky L, Trifiro MA. Interactions between androgen and estrogen receptors and the effects on their transactivational properties. Mol Cell Endocrinol. 2000;167:139–50.
Lanzino M, De Amicis F, McPhaul MJ, Marsico S, Panno ML, Ando S. Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells. J Biol Chem. 2005;280:20421–30.
Poulin R, Simard J, Labrie C, Petitclerc L, Dumont M, Lagace L, et al. Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line. Endocrinology. 1989;125:392–9.
Peters AA, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM, et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res. 2009;69:6131–40.
Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002;20:751–7.
Anderson TJ, Dixon JM, Stuart M, Sahmoud T, Miller WR. Effect of neoadjuvant treatment with anastrozole on tumour histology in postmenopausal women with large operable breast cancer. Br J Cancer. 2002;87:334–8.
Dowsett M. Preoperative models to evaluate endocrine strategies for breast cancer. Clin Cancer Res. 2003;9:502s–10s.
Miller WR, Jackson J. The therapeutic potential of aromatase inhibitors. Expert Opin Investig Drugs. 2003;12:337–51.
Takagi K, Miki Y, Nagasaki S, Hirakawa H, Onodera Y, Akahira J, et al. Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment. Endocr Relat Cancer. 2010;17:415–30.
Prat A, Karginova O, Parker JS, Fan C, He X, Bixby L, et al. Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes. Breast Cancer Res Treat. 2013;142:237–55.
Martin LA, Farmer I, Johnston SR, Ali S, Dowsett M. Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation. Endocr Relat Cancer. 2005;12(Suppl 1):S75–84.
Murphy CS, Pink JJ, Jordan VC. Characterization of a receptor-negative, hormone-nonresponsive clone derived from a T47D human breast cancer cell line kept under estrogen-free conditions. Cancer Res. 1990;50:7285–92.
Sabnis GJ, Jelovac D, Long B, Brodie A. The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation. Cancer Res. 2005;65:3903–10.
Santen RJ, Song RX, Masamura S, Yue W, Fan P, Sogon T, et al. Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells. Adv Exp Med Biol. 2008;630:19–34.
Fujiki N, Konno H, Kaneko Y, Gohno T, Hanamura T, Imami K, et al. Estrogen response element-GFP (ERE-GFP) introduced MCF-7 cells demonstrated the coexistence of multiple estrogen-deprivation resistant mechanisms. J Steroid Biochem Mol Biol. 2014;139:61–72.
Santner SJ, Chen S, Zhou D, Korsunsky Z, Martel J, Santen RJ. Effect of androstenedione on growth of untransfected and aromatase-transfected MCF-7 cells in culture. J Steroid Biochem Mol Biol. 1993;44:611–6.
Sasano H, Ozaki M. Aromatase expression and its localization in human breast cancer. J Steroid Biochem Mol Biol. 1997;61:293–8.
Hanamura T, Niwa T, Nishikawa S, Konno H, Gohno T, Tazawa C, et al. Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism. Breast Cancer Res Treat. 2013;139:731–40.
Fujii R, Hanamura T, Suzuki T, Gohno T, Shibahara Y, Niwa T, et al. Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma. J Steroid Biochem Mol Biol. 2014;144(Pt B):513–22.
Higuchi T, Endo M, Hanamura T, Gohno T, Niwa T, Yamaguchi Y, et al. Contribution of estrone sulfate to cell proliferation in aromatase inhibitor (AI) -resistant, hormone receptor-positive breast cancer. PLoS One. 2016;11:e0155844.
Brodie A, Sabnis G. Adaptive changes result in activation of alternate signaling pathways and acquisition of resistance to aromatase inhibitors. Clin Cancer Res. 2011;17:4208–13.
Macedo LF, Sabnis GJ, Goloubeva OG, Brodie A. Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. Cancer Res. 2008;68:3516–22.
Sabnis G, Brodie A. Adaptive changes results in activation of alternate signaling pathways and resistance to aromatase inhibitor resistance. Mol Cell Endocrinol. 2011;340:142–7.
Sasano H, Suzuki T, Miki Y, Moriya T. Intracrinology of estrogens and androgens in breast carcinoma. J Steroid Biochem Mol Biol. 2008;108:181–5.
Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX, et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003;24:152–82.
Labrie F. Intracrinology. Mol Cell Endocrinol. 1991;78:C113–8.
Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997;138:863–70.
Wang P, Wen Y, Han GZ, Sidhu PK, Zhu BT. Characterization of the oestrogenic activity of non-aromatic steroids: are there male-specific endogenous oestrogen receptor modulators? Br J Pharmacol. 2009;158:1796–807.
Aspinall SR, Stamp S, Davison A, Shenton BK, Lennard TW. The proliferative effects of 5-androstene-3 beta,17 beta-diol and 5 alpha-dihydrotestosterone on cell cycle analysis and cell proliferation in MCF7, T47D and MDAMB231 breast cancer cell lines. J Steroid Biochem Mol Biol. 2004;88:37–51.
Honma N, Saji S, Hirose M, Horiguchi S, Kuroi K, Hayashi S, et al. Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3beta, 17beta-diol. Cancer Sci. 2011;102:1848–54.
Sikora MJ, Cordero KE, Larios JM, Johnson MD, Lippman ME, Rae JM. The androgen metabolite 5alpha-androstane-3beta,17beta-diol (3betaAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance. Breast Cancer Res Treat. 2009;115:289–96.
Geisler J, Sasano H, Chen S, Purohit A. Steroid sulfatase inhibitors: promising new tools for breast cancer therapy? J Steroid Biochem Mol Biol. 2011;125:39–45.
Purohit A, Woo LW, Potter BV. Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism. Mol Cell Endocrinol. 2011;340:154–60.
Hanamura T, Niwa T, Gohno T, Kurosumi M, Takei H, Yamaguchi Y, et al. Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers. Breast Cancer Res Treat. 2014;143:69–80.
Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2:101–12.
Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996;15:2174–83.
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995;270:1491–4.
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001;276:9817–24.
Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, et al. A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology. 2000;141:4503–11.
Shim WS, Conaway M, Masamura S, Yue W, Wang JP, Kmar R, et al. Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo. Endocrinology. 2000;141:396–405.
Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446–51.
Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.
Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34:2961–8.
Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2:1310–5.
Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, et al. ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 2011;1:338–51.
Tilghman SL, Townley I, Zhong Q, Carriere PP, Zou J, Llopis SD, et al. Proteomic signatures of acquired letrozole resistance in breast cancer: suppressed estrogen signaling and increased cell motility and invasiveness. Mol Cell Proteom. 2013;12:2440–55.
Hayashi S, Kimura M. Mechanisms of hormonal therapy resistance in breast cancer. Int J Clin Oncol. 2015;20:262–7.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–67.
Ni M, Chen Y, Lim E, Wimberly H, Bailey ST, Imai Y, et al. Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell. 2011;20:119–31.
Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14:989–98.
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28:4594–600.
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106:djt337.
Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30:870–84.
Stanway SJ, Purohit A, Woo LW, Sufi S, Vigushin D, Ward R, 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. 2006;12:1585–92.
Purohit A, Foster PA. Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers. J Endocrinol. 2012;212:99–110.
Williams CJ, Barley VL, Blackledge GR, Rowland CG, Tyrrell CJ. Multicentre cross over study of aminoglutethimide and trilostane in advanced postmenopausal breast cancer. Br J Cancer. 1993;68:1210–5.
Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:811–21.
Massacesi C, Di Tomaso E, Urban P, Germa C, Quadt C, Trandafir L, et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 2016;9:203–10.
Zaman K, Winterhalder R, Mamot C, Hasler-Strub U, Rochlitz C, Mueller A, et al. Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: a multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08. Eur J Cancer. 2015;51:1212–20.
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425–39.
Sabnis GJ, Goloubeva OG, Kazi AA, Shah P, Brodie AH. HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2. Mol Cancer Ther. 2013;12:2804–16.
Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31:2128–35.
Fioretti FM, Sita-Lumsden A, Bevan CL, Brooke GN. Revising the role of the androgen receptor in breast cancer. J Mol Endocrinol. 2014;52:R257–65.
O’Shaughnessy J, Campone M, Brain E, Neven P, Hayes D, Bondarenko I, et al. Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Ann Oncol. 2016;27:106–13.
Li W, O’Shaughnessy JA, Hayes DF, Campone M, Bondarenko I, Zbarskaya I, et al. Biomarker associations with efficacy of abiraterone acetate and exemestane in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22:6002–9.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Hanamura, T., Hayashi, Si. Overcoming aromatase inhibitor resistance in breast cancer: possible mechanisms and clinical applications. Breast Cancer 25, 379–391 (2018). https://doi.org/10.1007/s12282-017-0772-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12282-017-0772-1