FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer
Menée à l'aide de lignées cellulaires de cancer du sein résistant aux traitements endocriniens, cette étude met en évidence un mécanisme par lequel la surexpression du facteur nucléaire de transcription FOXA1, en induisant la modification des régions amplificatrices de l'ensemble du génome, favorise l'activation de programmes transcriptionnels pro-métastatiques
FOXA1 augmentation, including by genetic aberrations, drives aggressive phenotypes of estrogen receptor-positive (ER+) breast cancer (BC). Here, we show that FOXA1 upregulation induces genome-wide enhancer reprogramming and adopts a superenhancer mechanism to activate the master transcription factor HIF-2α and a prometastatic transcriptional program. The hyperactive FOXA1/HIF-2α transcriptional axis is observed to be largely nonconcurrent with the ESR1 mutations in clinical ER+/HER2− metastatic BC datasets, suggesting different mechanisms of resistance. Furthermore, a selective HIF-2α inhibitor, currently in clinical trials for advanced renal cell carcinoma and glioblastoma, inhibits the clonogenicity, migration, and invasion of endocrine-resistant BC cells. These findings demonstrate the role of FOXA1 upregulation in enhancer reprogramming and a therapeutic approach of targeting deregulated transcriptional programs to circumvent endocrine-resistant metastatic BC.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 the ESR1 mutations, 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.