Abstract 4756: Elucidating the role of AR in breast cancer .
Authors: D'Amato Nicholas C. , Gu Haihua , Cochrane Dawn R. , Bernales Sebastian , Jacobsen Britta M. , Jedlicka Paul , Torkko Kathleen C. , Edgerton Susan M. , Thor Ann D. , Elias Anthony D. , Protter Andrew A. , Richer Jennifer K. 
Published: August 2014

Background: In breast cancers, the androgen receptor (AR) is more widely expressed than estrogen receptor alpha (ER) or progesterone receptor (PR), and AR has recently emerged as a useful marker for refinement of breast cancer subtype classification. Approximately 77% of invasive breast cancer tumors are positive for AR and among the subtypes, 88% of ER+, 59% of HER2+, and 32% of triple negative breast cancers (ER-/PR-/HER2-) are positive for AR protein expression by IHC. AR expression has been associated with resistance to current endocrine therapies (tamoxifen and aromatase inhibitors) in cell line and preclinical models, and clinical studies.

Hypothesis: We hypothesized that ER+ breast cancers that become resistant to traditional endocrine therapies might do so by switching from estrogen to androgen-dependence and that AR holds potential as a therapeutic target in AR+ breast cancers, whether ER+ or ER-.

Methods: We quantified the percentage of cells positive for nuclear AR compared to the percentage of cells positive for ER in a cohort of tamoxifen treated patients with clinical outcome data. We also examined the effect of dihydrotestosterone (DHT) and estradiol (E2) in the presence of enzalutamide (formerly MDV3100), a novel AR inhibitor, in in vitro and in vivo models of ER+, ER-, and Her2+ breast cancer that retain AR.

Results: Our clinical data indicate that a high ratio of AR to ER protein is indicative of a shorter time to relapse in patients treated with tamoxifen and a lack of response to neo-adjuvant AI treatment. In ER+ models, bicalutamide and enzalutamide both inhibit DHT-mediated proliferation, while enzalutamide uniquely inhibited E2-mediated proliferation. In xenograft tumor studies, enzalutamide significantly reduced estrogen- and androgen-mediated growth of ER+/AR+ xenograft tumors. Remarkably, enzalutamide demonstrated an anti-proliferative effect comparable to tamoxifen on tumors in E2 treated mice and inhibited the expression of classic E2-regulated genes such as SDF-1. Enzalutamide opposed DHT-stimulated proliferation of ER-/AR+ MDA-MB-453 tumors in vivo and caused decreased nuclear AR localization and increased tumor cell apoptosis. In Her2+ breast cancer cell lines, enzalutamide enhanced the response to trastuzumab and decreased the amount of both phosphorylated and total Her3.

Conclusions: Enzalutamide demonstrated significant anti-tumor activity in preclinical models of breast cancers that express AR, regardless of ER status. In Her2+ breast cancer, inhibition of AR with enzalutamide may enhance response to Her2-directed therapy or overcome resistance to such agents by reducing levels of Her3. The AR:ER ratio may be a new predictor of response to traditional E2/ER directed endocrine therapy and may indicate that patients who relapse while on tamoxifen or AIs might be good candidates for AR-directed therapy.

Citation Format: Nicholas C. D'Amato, Haihua Gu, Dawn R. Cochrane, Sebastian Bernales, Britta M. Jacobsen, Paul Jedlicka, Kathleen C. Torkko, Susan M. Edgerton, Ann D. Thor, Anthony D. Elias, Andrew A. Protter, Jennifer K. Richer. Elucidating the role of AR in breast cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4756. doi:10.1158/1538-7445.AM2013-4756