Abstract A047: Targeting androgen receptor decreases proliferation of triple-negative breast cancer

Abstract

Abstract Recent studies demonstrate that the androgen receptor (AR) is expressed in up to a third of triple negative breast cancer (TNBC) and define a subtype of TNBC with a “luminal AR” gene signature. We hypothesized that AR+TNBC are dependent on AR for growth and that inhibiting AR activity by preventing nuclear localization and DNA binding will decrease proliferation and tumor burden in preclinical models of breast cancer. Indeed, knock down of AR expression using a lentiviral shRNA significantly reduced proliferation in cell line models of TNBC compared to cells transduced with a non-targeting control (2-fold reduction, p<0.001). Propidium iodide cell cycle analysis demonstrated that TNBC cells with reduced AR expression had a 22% increase in the percentage of cells in S-phase (p<0.001). In TNBC cells that exhibit androgen-stimulated growth, reduced AR expression inhibited response to ligand. Enzalutamide, an AR inhibitor, inhibited ligand mediated nuclear translocation of AR as assessed by nuclear cytosolic fractionation and significantly decreased baseline proliferation of TNBC in vitro (p<0.001). In MDA453 xenografts, enzalutamide significantly decreased tumor volume and weight by up to 85% and increased apoptosis as measured by cleaved caspase-3 by 60% compared to mice that received DHT alone. In addition, a 50% reduction in nuclear AR was observed in the tumors of mice treated with enzalutamide. Thus AR may play an important role in a subset of TNBC and presents an opportunity for targeted therapy. Citation Format: Valerie Barton, Nicholas D'Amato, Jennifer Richer. Targeting androgen receptor decreases proliferation of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A047.