GSE157862
A Positive Feedback Loop Between TGFß and Androgen Receptors Supports Triple-Negative Breast Cancer Anoikis Resistance
Triple-negative breast cancer (TNBC) is an aggressive subtype with few treatment options for chemo-resistant disease. In both preclinical models and patient circulating tumor cells, androgen receptor (AR) expression is increased in anchorage independent TNBC. The AR inhibitor enzalutamide (Enza) leads to reduced TNBC growth in soft agar, invasion, mammosphere formation in vitro, and reduced tumorigenicity and recurrence when combined with chemotherapy in vivo pre-clinical models. Transforming growth factor ß (TGFß) pathway gene signatures are also increased during TNBC anchorage independent survival both in vitro and in vivo in pre-clinical models and CTC from patients during relapse while on chemotherapy. We hypothesized that a positive loop between AR and TGFß signaling facilitates TNBC anchorage independent survival (anoikis resistance). We previously published that AR protein levels and transcriptional activity increased during anchorage independent conditions and we now find that that multiple components of the TGFß pathway, including TGFß1 and 3, as well as pathway activity, as measured by nuclear localization and transcriptional activity of pSmad3, are enhanced in anchorage independent conditions. Indeed, exogenous TGFß increased AR protein and TGFß inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-Seq experiments revealed AR binding to genomic regions near the TGFB1 and SMAD3. TGFB3 and AR expression were positively correlated in clinical datasets and high levels of co-expression correspond to significantly worse recurrence-free and overall survival in both ER- and basal-like breast cancer. Finally, combining Enza with a TGFß inhibitor decreased cell survival more than either drug alone, particularly under anchorage independent conditions, where the effect was more than additive. These findings warrant further investigations into whether combined inhibition of AR and TGFß pathways might decrease metastatic recurrence rates and mortality from TNBC. Overall design: ChIP-seq of androgen receptor in MDA-MB-453 attached and suspension cultures treated with dihydrotestosterone and enzalutamide.