Estrogen receptor beta increases sensitivity to enzalutamide in androgen receptor-positive triple-negative breast cancer

PurposeAndrogen receptor (AR) is playing an important role in the progression of a subset of TNBC. We evaluated the impact of ER expression along with anti-AR drugs in AR-positive TNBC.MethodsER expression was examined in AR-positive TNBC cell line using MTT assay, scratch and Annexin V-FITC assay in the presence or absence of anti-androgens. Protein levels of involved molecules were assessed using Western blot. Receptors' localization was detected by immunofluorescence and their physical association was examined using proximity ligation assay (PLA), which enables the visualization of interacting proteins in fixed cells and tissues.ResultsTransient transfection of ER in MDA-MB 453 AR-positive TNBC cell line significantly inhibited cell proliferation, metastatic potential and induced apoptosis. ER expression reversed the aggravating role of AR in both indirect and direct ways. Indirectly, ER decreased AR activation through the inhibition of PI3K/AKT signaling pathway. Directly, ER formed heterodimers with AR in MDA-MB 453 cells and in human tissue samples impeding AR from forming homodimers. Enzalutamide is a more potent anti-androgen in AR+TNBC compared to bicalutamide. ER expression increased the sensitivity of MDA-MB 453 cells to anti-androgens and especially to enzalutamide. The administration of enzalutamide enhanced AR:ER heterodimers formation increasing the anti-tumor capacity of ER.ConclusionsCollectively, our results provide evidence for a novel mechanism by which ER exerts oncosuppressive effect in AR-positive TBNC through direct and indirect interactions with AR. Moreover, ER expression may identify a new subset of TNBC that would respond more favorable to anti-androgens.