Abstract P6-05-04: Expression of the Androgen Receptor in triple negative tumors and its modulation by receptor tyrosine kinases and downstream pathways

Abstract

Abstract Background: Androgen receptor (AR) plays a central role in some tumor types like prostate cancer. Its expression and function in breast cancer is relatively unknown. Studies have linked tyrosine kinase (TK) receptors and their intracellular signaling pathways with AR status. In the present work we study the presence of AR in breast cancer human samples and how TKs can control its expression. Methods: Tumor samples from patients were used to assess the expression of AR by western-blot. Membrane and intracellular kinases were evaluated using phosphoprotein arrays. Cell lines representative of all breast cancer subtypes were used to assess the expression of the AR and other signaling proteins using western-blot and phosphoprotein arrays. Proliferation studies with several kinase inhibitors were measured by MTT assays. We also interrogated publicly available gene expression microarray data sets with annotated clinical-pathological data. Results: Across all the intrinsic subtypes of breast cancer, the expression of AR gene was found highly expressed in HER2-enriched and Luminal tumors and lowly expressed in Basal-like and/or triple-negative (TN) tumors. In TN tumors, PDGFRβ and EGFR were found highly activated, together with AKT and Erk1/2. A positive correlation was observed between activation of EGFR and PDGFRβ and the expression of AR. In vitro, AR protein expression varied across cell lines and was found more expressed in MCF7 (Luminal) and HS578T (TN), BT549 (TN), HCC70 (TN) and no expressed in HBL100 (TN) and MDA-MB231 (TN). Administration of the antiandrogen bicalutamide produced an anti-proliferative effect that was increased by association of an Erk1/2 inhibitor. Inhibition of the PI3K-mTOR pathway in BT549 and HS578T reduced the expression of AR but did not augment the action of bicalutamide. In TN tumors, AR gene and protein was found more expressed in older compared to younger patients. Conclusions: In breast cancer, AR is expressed and is controlled by receptor TKs through the PI3K-mTOR pathway. An increased anti-proliferative effect is observed with the combination of bicalutamide and Erk1/2 inhibitors. AR expression correlates with age at diagnosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-04.