Effect of MDV3100, an androgen receptor signaling inhibitor, on tumor growth of estrogen and androgen receptor-positive (ER+/AR+) breast cancer xenografts.

Abstract

564 Background: The androgen receptor (AR) is detected by immunohistochemistry in approximately 75% of all invasive breast cancer; with ~88% of ER+ tumors expressing AR. Potent inhibition of AR activity could be a therapeutic strategy in ER+/AR+ breast cancer. MDV3100 is an androgen receptor signaling inhibitor (ARSI), which inhibits AR activity via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. MDV3100 has demonstrated an overall survival benefit in men with post-docetaxel prostate cancer. Methods: Two ER+/AR+ breast cancer cell lines, MCF7 and BCK4 (recently derived from a pleurocentesis), were used to assess the proliferative effect of dihydrotestosterone (DHT) and estradiol (E2). The efficacy of MDV3100 at blocking DHT-mediated proliferation was compared to bicalutamide in ER+/AR+ breast cancer cells. MCF7 xenograft studies were performed to determine if MDV3100 can affect DHT or E2 mediated proliferation in vivo. Results: Both bicalutamide and MDV3100 inhibited DHT-mediated proliferation of ER+/AR+ cell lines. Although MDV3100 binds AR very effectively and does not bind ER, it also uniquely inhibited E2-mediated proliferation, while bicalutamide slightly enhanced E2 mediated proliferation. Results presented here demonstrate that MDV3100 inhibited E2-stimulated tumor growth of MCF7 mammary xenografts as effectively as tamoxifen. Conclusions: MDV3100 blocked both DHT- and E2-mediated growth of breast cancer cells, whereas bicalutamide enhanced E2-mediated proliferation. MDV3100 may have unique therapeutic utility in patients with AR+ breast cancer, regardless of ER status. Funding: DOD Breast Cancer Program Idea Award BC074403, Avon Foundation for Women, and University of Colorado Cancer Center pilot project funds to JKR.