GSE124654
FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer [ChIP-seq]
Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Here, we have demonstrated that FOXA1 overexpression in estrogen receptor-positive breast cancer cells drives genome-wide enhancer reprogramming to activate pro-metastatic transcriptional programs. Specifically, FOXA1 overexpression generated more gained chromatin binding regions than the lost regions with decreased FOXA1 binding. Furthermore, FOXA1 overexpression led to establishment of more gained enhancers marked with increased H3K27ac and/or H3K4me1 than the lost enhancers with decreased signals of these two histone marks. In addition, these altered enhancers were highly coordinated with FOXA1-chromatin binding (cistrome) and the alteration of transcriptome due to FOXA1 overexpression, suggesting the direct engagement of high FOXA1 in enhancer reprogramming. The coordination between FOXA1 cistrome, enhancer reprogramming, and transcriptome also exists in the tamoxifen-resistant MCF7 cell model with endogenous FOXA1 gene amplification. Overall, our study supports the notion that FOXA1 overexpression promotes enhancer reprogramming in ER-positive breast cancer to activate gene expression associated with endocrine resistance and metastasis. Overall design: Examination of FOXA1-chromatin binding and 2 different enhancer histone modifications in endocrine-sensitive and resistant breast cancer cell models.