Breast cancer is a heterogeneous disease with distinct subtypes that are predictive of patient prognosis. Luminal subtype tumors confer the most favorable prognosis due to ERα-positivity and response to endocrine therapies. In contrast, basal-like subtype tumors confer the worst prognosis due to intrinsic resistance to chemotherapy and the lack of targeted therapies. The forkhead box transcription factor, FOXA1, is found exclusively in luminal tumors, and positively correlates with ERα and survival. Prior to our study, FOXA1 was known to mediate the development of many tissues and be required for ERα transcriptional activity in breast cancer cells. Given these findings, along with the requirement for ERα in mammary morphogenesis, we hypothesized that FOXA1 would be similarly necessary in this process. Using Foxa1 null mice, we found FOXA1 is required for hormone-induced ductal invasion. Mammary glands null for Foxa1 lack epithelial ERα. The regulation of ERα by FOXA1 is similarly observed in breast cancer cells. These results revealed that FOXA1 is not only required for ERα activity, but also for its expression, and provided a mechanism for the ductal phenotype in Foxa1 knockout glands.
The positive correlation between FOXA1 and ERα in breast tumors is significant, but not perfect. FOXA1 is also expressed in luminal breast tumors and cell lines in the absence of ERα prompting us to investigate an ERα-independent role for FOXA1 in maintaining the luminal subtype. FOXA1 silencing in ERα-positive and ERα-negative luminal breast cancer cells decreases luminal gene expression, and concomitantly increases basal gene expression. These cells are also more aggressive in vitro, indicating a shift toward the basal phenotype. FOXA1 binds to a subset of basal genes, and thus, is likely orchestrating repression of these genes at the transcriptional level. These data implicate FOXA1 as a mediator of breast cellular plasticity, and suggest that therapeutically reducing FOXA1 in luminal tumors will increase disease aggressiveness. Combined, this dissertation research has detailed the role for FOXA1 in the normal mammary gland and its importance in luminal breast cancer. Our results have led to numerous testable hypotheses that will continue to advance our understanding of FOXA1 in breast cancer.