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

Autor: Jorge S. Reis-Filho, Nikhil Wagle, Ofir Cohen, Sepideh Mehravaran, Jamunarani Veeraraghavan, Resel Pereira, Myles Brown, Lanfang Qin, Bert W. O'Malley, Carmine De Angelis, Carolina Gutierrez, Vidyalakshmi Sethunath, Xiaoyong Fu, Rachel Schiff, Maria Letizia Cataldo, Sarmistha Nanda, Qin Feng, Mothaffar F. Rimawi, Gary C. Chamness, Rinath Jeselsohn, Britta Weigelt, Pier Selenica, Agostina Nardone, C. Kent Osborne
Přispěvatelé: Fu, X., Pereira, R., De Angelis, C., Veeraraghavan, J., Nanda, S., Qin, L., Cataldo, M. L., Sethunath, V., Mehravaran, S., Gutierrez, C., Chamness, G. C., Feng, Q., O'Malley, B. W., Selenica, P., Weigelt, B., Reis-Filho, J. S., Cohen, O., Wagle, N., Nardone, A., Jeselsohn, R., Brown, M., Rimawi, M. F., Osborne, C. K., Schiff, R.
Rok vydání: 2019
Předmět:
Zdroj: Proc Natl Acad Sci U S A
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.1911584116
Popis: 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.
Databáze: OpenAIRE
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