Estrogen receptor negative (ER-) breast cancer remains the major therapeutic challenge for breast cancer treatment and a better understanding of the mechanisms underlying the progression of this disease is necessary to develop efficient therapeutic strategies. The molecular apocrine breast cancer subtype lacks ER expression but is characterised by the expression of the androgen receptor (AR). In prostate cancer, the forkhead transcription factor FoxA1 is a key determinant of AR cistrome but is not essential for AR binding to DNA. In breast cancer, FoxA1 is also a key determinant of ER cistrome but is essential for ER to bind DNA. In the molecular apocrine breast cancer context, AR and FoxA1 have been shown to maintain an ER-like breast cancer phenotype. Whether FoxA1 is required for AR to bind DNA in molecular apocrine breast cancer cells is unknown and has not been previously explored.
We show that FoxA1 was required for cell growth but not for AR binding to chromatin in a molecular apocrine breast cancer context. In the absence of FoxA1, AR cistrome was expanded in the MDA-MB-453 model of molecular apocrine breast cancer, with a gain of new AR binding events. Proteomic analysis showed a significant change in AR chromatin protein-bound complex in the absence of FoxA1. AP2a motifs were enriched at AR binding sites gained without FoxA1 and quantitative proteomic comparison of the AR chromatin-bound complex confirmed an increased interaction between AP2a and AR in the absence of FoxA1.
Our findings indicate that FoxA1 is not required for AR to bind DNA in molecular apocrine breast cancer cells. In the absence of FoxA1, AR interacts with AP2a to induce a new phenotype with features of a secretory cell while maintaining luminal characteristics. The deeper understanding of AR signaling in ER- breast cancer could open avenues for new therapeutic strategies.