FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer

Abstract

Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2−metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with theESR1mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.

HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

“…Downstream targets of the HIF isoforms (HIF-1 and HIF-2) only partially overlap, and in breast cancer, HIF-1 is the predominantly (over)expressed isoform (7,8). Recently, specific roles for HIF-2 in breast cancer progression, mediated upstream by the transcription factor FOXA1, and angiogenesis have been identified (9,10). In human breast tumors, HIF-1 is already overexpressed in precursor lesions (ductal carcinoma in situ [DCIS]) and earlystage breast cancer, and these levels strongly correlate with tumor grade and invasion (11).…”

“…Multiple other metabolites and HIF-induced metabolic enzymes are involved in feed-forward loops with HIF activity in normoxia, including ROS, acetyl-CoA synthetase (ACSS2), and mitochondrial proteins such as CHCHD4 (4,(30)(31)(32)(33) (Figure 1). HIF expression, stability, and effector function at HREs are additionally influenced by other (bidirectional) processes such as epigenetics, the circadian rhythm, non-coding RNAs, and HIF-dependent secretion of microvesicles by tumor cells or cells in the tumor microenvironment (TME) (9,(34)(35)(36)(37)(38). For instance, tumor-associated macrophages secrete vesicles containing the long non-coding RNA HISLA, which blocks the PHD/HIF-1 interaction and induces glycolysis in normoxic breast cancer cells (35).…”

“…SNAT2 knockdown reversed tamoxifen resistance and dampened signaling through the mTOR pathway, the latter being a known resistance mechanism to anti-estrogen therapy (66). Other reports also describe a HIF-2 and/or SLC7A5/mTOR regulatory axis underlying endocrine resistance (9,67). In addition, contralateral breast cancers developing during adjuvant tamoxifen treatment, i.e.…”

miR‑132 is upregulated in polycystic ovarian syndrome and inhibits granulosa cells viability by targeting Foxa1

“…Foxa1 is a transcription factor that belongs to the forkhead family, consisting of the winged-helix dna-binding domain, and the n-terminal and c-terminal transcriptional domains, thereby delineating genomic regions and allowing for the subsequent binding of other transcription factors, such as the estrogen receptor, progesterone receptor and androgen receptor (27)(28)(29). Foxa1 is expressed in a variety of organs, including breast, liver, pancreas and prostate, and can influence the expression of a large number of genes associated with metabolic processes, the regulation of signaling and the cell cycle (30,31).…”

miR-132 is up-regulated in polycystic ovarian syndrome and inhibits granulosa cells proliferation via targeting Foxa1

“…Forkhead box protein A1 (FOXA1) is a transcription factor that belongs to the forkhead family consisting of the winged-helix DNA-binding domain and the N-terminal and C-terminal transcriptional domains, thereby delineating genomic regions and allowing for subsequent binding of other transcription factors, such as the ER, progesterone receptor (PR), and androgen receptor (AR) [26][27][28].…”