Abstract P3-04-02: Multiple subtypes of triple negative breast cancer are dependent on androgen receptor

Abstract

Abstract Triple negative breast cancer (TNBC) constitutes 10-20% of invasive breast carcinomas and has the lowest five-year survival rate. Currently, there are no targeted therapies for TNBC. Recent studies demonstrate that the androgen receptor (AR) is expressed in up to a third of TNBC. AR is highly expressed in the "luminal AR (LAR)" molecular TNBC subtype, but is also present in other TNBC subtypes and may present an opportunity for targeted therapy. We hypothesized that AR+ TNBC critically depend on AR and that AR inhibition will decrease tumor burden in preclinical models of breast cancer. To determine the extent to which AR+ TNBC depend on AR, we inhibited AR activity with the AR antagonist enzalutamide (ENZ) and shRNAs against AR in multiple TNBC subtypes. Treatment with ENZ prevented AR nuclear localization in response to DHT in multiple TNBC cell lines, reduced baseline proliferation in 2D culture (p<0.05), and decreased anchorage independent growth in soft agar (p<0.01). AR knockdown significantly reduced proliferation (p<0.001) and increased apoptosis (p<0.001) compared to cells transduced with a non-targeting control. In addition to reduced proliferation, AR knockdown or treatment with ENZ altered cellular morphology from stellate to round in Matrigel and significantly decreased migration (p<0.05) and invasion (p<0.001) of cell lines spanning multiple TNBC subtypes. Microarray profiling and ELISA of TNBC lines treated with DHT and ENZ suggested that AR regulation of the EGFR ligand amphiregulin (AREG, p<0.05) is a mechanism by which AR influences proliferation, migration and invasion in TNBC. Indeed, treatment with exogenous AREG rescued decreased proliferation, migration and invasion of AR knockdown cell lines (p<0.05). In vivo, ENZ significantly decreased tumor viability (p=0.008) and increased necrosis (p=0.009) in SUM159PT xenografts. Our findings suggest that AR influences both proliferation and invasion of AR+ TNBC cells representing multiple TNBC subtypes and provide promising preclinical data on the efficacy of ENZ in AR+ TNBC. Thus, inhibition of AR by anti-androgens such as ENZ may represent an effective targeted therapy for TNBC. Citation Format: Valerie N Barton, Nicholas C D'Amato, Michael A Gordon, Britta M Jacobsen, Jennifer K Richer. Multiple subtypes of triple negative breast cancer are dependent on androgen receptor [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-04-02.