FOXA2 as a SETD1A-Regulated Driver of Tamoxifen Resistance in Breast Cancer

Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor (ER) α-positive breast cancer; however, resistance remains a significant clinical challenge. This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer, with particular focus on the role of SET Domain Containing 1A (SETD1A)-driven forkhead box A2 (FOXA2) as a key regulator of this resistance.

FOXA2 expression and its regulation by SETD1A were assessed via (quantitative polymerase chain reaction), western blotting, transcriptome profiling, and chromatin immunoprecipitation analyses. The effects of FOXA2 on cell proliferation, migration, invasion, and cancer stem cell traits were evaluated using small interfering RNA (siRNA)-mediated silencing. Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.

FOXA2 expression was significantly elevated in tamoxifen-resistant (TamR) and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells, regardless of tamoxifen treatment or ERα depletion. Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A, a histone methyltransferase, directly regulated FOXA2 expression. Functionally, FOXA2 knockdown inhibited the proliferation, migration, invasion, and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity. High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.

Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.