FOXA1 is a key determinant of estrogen receptor function and endocrine response

Abstract

Estrogen Receptor-α (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3α). We now show that FOXA1 is a critical determinant that can influence differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 influences genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells can alter ER binding and function. As such, FOXA1 is a major determinant of estrogen-ER activity and endocrine response in breast cancer cells.

Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology

“…In addition, silencing of FOXA1 affected the expression of estrogenresponsive genes. Hurtado et al also showed that FOXA1 is necessary for ERα binding in tamoxifen-regulated gene expression in breast cancer cells and that most ER binding sites overlap between estrogen-and tamoxifen-treated cells, implying that FOXA1 also plays a role in tamoxifenmediated transcriptional regulation of ERα [68] . Moreover, they performed formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIREseq) to identify nucleosome-free and dense chromatin regions in MCF-7 cells and showed that ERα binds to nucleosomedense regions in combination with FOXA1 [68] .…”

“…Moreover, they performed formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIREseq) to identify nucleosome-free and dense chromatin regions in MCF-7 cells and showed that ERα binds to nucleosomedense regions in combination with FOXA1 [68] . In addition to the finding that the binding of FOXA1 to ERE is essential for establishing stable recruitment of ER to EREs [68][69][70][71][72] , these observations support the notion that the FOXA1 transcription factor functions as a pioneer factor for ER.…”

“…They identified the 10 205 E2-regulated ERBSs in MCF-7 cells and showed that tamoxifen and fulvestrant partially decrease the binding of ERα and RNA polymerase II around the E2-upregulated genes [66,67] . To examine the role of FOXA1 in ERα binding, Hurtado et al performed ChIPseq analysis of ER binding sites in MCF-7 cells in which FOXA1 was silenced with short interfering RNAs (siRNAs) [68] . Silencing of FOXA1 decreased the binding intensity at ERBSs that are in the vicinity of FOXA1 binding sites.…”

Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review)

“…The interaction of FOXA1 with the cis-regulatory regions of heterochromatin enhances the binding of ERα to DNA (28) and is involved in controlling almost 50% of the estrogen receptor target genes (29,30). The expression of FOXA1 is significantly positively correlated with the markers of good prognosis or ER-positivity (31) and FOXA1 was recently shown to be required for almost all the ER-binding events in breast cancer cells (32). The transcription factor GATA-3 was recently identified as a key factor involved in luminal cell differentiation in the mammary gland (33).…”

A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects

“…[29][30][31][32][33] Presence of the variant allele (T) increases the chromatin's affinity for FOXA1, 34 a pioneer factor that can bind to chromatin and recruit the ER, thereby facilitating estrogen-driven transcription and cellular changes. 35 The other highly ranked TOX3 SNP, rs3803662:G4A, was also originally identified in a GWAS study 36 and the association was successfully replicated. [37][38][39][40] The top two ranked SNPs from the maternal effects analysis, rs12919267:C4T and rs12926526:A4G, are in RBFOX1, which encodes the FOX1 RNA-binding protein.…”