Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide

被引：315

作者：

Cochrane, Dawn R. ^{[1
]}

Bernales, Sebastian ^{[2
,3
]}

Jacobsen, Britta M. ^{[1
]}

Cittelly, Diana M. ^{[1
]}

Howe, Erin N. ^{[1
]}

D'Amato, Nicholas C. ^{[1
]}

Spoelstra, Nicole S. ^{[1
]}

Edgerton, Susan M. ^{[1
]}

Jean, Annie ^{[1
]}

Guerrero, Javier ^{[3
]}

Gomez, Francisco ^{[3
]}

Medicherla, Satyanarayana ^{[2
]}

Alfaro, Ivan E. ^{[3
]}

McCullagh, Emma ^{[2
,3
]}

Jedlicka, Paul ^{[1
]}

Torkko, Kathleen C. ^{[1
]}

Thor, Ann D. ^{[1
]}

Elias, Anthony D. ^{[4
]}

Protter, Andrew A. ^{[2
]}

Richer, Jennifer K. ^{[1
]}

机构：

[1] Univ Colorado, Dept Pathol, Aurora, CO 80045 USA

[2] Medivation Inc, San Francisco, CA 94105 USA

[3] Fdn Ciencia & Vida, Santiago 7780272, Chile

[4] Univ Colorado, Div Oncol, Dept Med, Aurora, CO 80045 USA

来源：

BREAST CANCER RESEARCH | 2014年 / 16卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NEOADJUVANT ENDOCRINE THERAPY; CELL-LINE; ESTROGEN-RECEPTORS; PROSTATE-CANCER; GROWTH; EXPRESSION; TAMOXIFEN; ANTIANDROGEN; RESISTANCE; INHIBITOR;

D O I：

10.1186/bcr3599

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Introduction: The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer. Methods: We examined nuclear AR to ER protein ratios in primary breast cancers in relation to response to endocrine therapy. The effects of AR inhibition with enzalutamide were examined in vitro and in preclinical models of ER positive and negative breast cancer that express AR. Results: In a cohort of 192 women with ER + breast cancers, a high ratio of AR:ER (>= 2.0) indicated an over four fold increased risk for failure while on tamoxifen (HR = 4.43). The AR:ER ratio had an independent effect on risk for failure above ER % staining alone. AR:ER ratio is also an independent predictor of disease-free survival (HR = 4.04, 95% CI: 1.68, 9.69; p = 0.002) and disease specific survival (HR = 2.75, 95% CI: 1.11, 6.86; p = 0.03). Both enzalutamide and bicalutamide inhibited 5-alpha-dihydrotestosterone (DHT)-mediated proliferation of breast cancer lines in vitro; however, enzalutamide uniquely inhibited estradiol (E2)-mediated proliferation of ER+/AR + breast cancer cells. In MCF7 xenografts (ER+/AR+) enzalutamide inhibited E2-driven tumor growth as effectively as tamoxifen by decreasing proliferation. Enzalutamide also inhibited DHT- driven tumor growth in both ER positive (MCF7) and negative (MDA-MB-453) xenografts, but did so by increasing apoptosis. Conclusions: AR to ER ratio may influence breast cancer response to traditional endocrine therapy. Enzalutamide elicits different effects on E2-mediated breast cancer cell proliferation than bicalutamide. This preclinical study supports the initiation of clinical studies evaluating enzalutamide for treatment of AR(+) tumors regardless of ER status, since it blocks both androgen- and estrogen- mediated tumor growth.

引用

页数：19

共 56 条

[31] Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor [J].