FOXA1 is required for ErbB2 expression and luminal differentiation in HER2-positive breast cancer [ATAC-seq]

Forkhead box protein A1 (FOXA1) has been shown to have critical functions in prostate and ER alpha positive breast cancer. As a pioneering transcriptional factor, FOXA1 regulates DNA accessibility for the androgen receptor in prostate and the estrogen receptor alpha in ER positive breast cancer, respectively. FOXA1 is also expressed in human epidermal growth factor receptor-2 (HER2/ErbB2) positive breast cancers, but its functions in HER2 positive breast cancer are unclear. The loss of FOXA1 results in a decrease in the viability of HER2 positive and HER2 amplified cell lines suggesting that FOXA1 may have an important role in HER2 positive breast cancers. In this report, we examined patient-derived single-cell RNA sequencing and spatial transcriptomics data and demonstrated that FOXA1 is co-expressed with ErbB2 in HER2 positive breast cancers. Knocking down FOXA1 expression led to the reduction of HER2 expression and signaling. Chromatin Immunoprecipitation Sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) identified FOXA1 binding motifs in the ErbB2 promoter and regulatory element regions, which controlled ErbB2 gene expression. Interestingly, the knockdown of FOXA1 increased Epithelial Mesenchymal Transition (EMT) signaling and inhibited luminal tumor differentiation. Furthermore, FOXA1 and TRPS1 regulated TEAD/YAP-TAZ activity. Taken together, our data demonstrate that FOXA1 is required for HER2 expression and luminal identity in HER2+ breast cancer.