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

   


Authors: 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.
Article Title: 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 receptorpositive (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 hypoxiainducible 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 endocrineresistant 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. © 2019 National Academy of Sciences. All rights reserved.
Keywords: controlled study; unclassified drug; gene mutation; human cell; drug efficacy; drug targeting; antineoplastic agent; protein function; gene; metastasis; breast cancer; hepatocyte nuclear factor 3alpha; gene expression; transcription initiation; embryo development; genetic transcription; cancer hormone therapy; oncogene; gene activation; cancer cell; cell migration; genome; upregulation; metastatic breast cancer; cell invasion; clonogenesis; enhancer region; clinical outcome; hypoxia inducible factor 2alpha; estrogen receptor positive breast cancer; human; priority journal; article; endocrine resistance; foxa1; esr1 gene; enhancer/transcriptional reprogramming; hypoxia inducible factor 2alpha antagonist; endocrine resistant breast cancer
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 116
Issue: 52
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2019-12-26
Start Page: 26823
End Page: 26834
Language: English
DOI: 10.1073/pnas.1911584116
PUBMED: 31826955
PROVIDER: scopus
PMCID: PMC6936436
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077266207&doi=10.1073%2fpnas.1911584116&partnerID=40&md5=c9f150c6c3ecc1d1ffde4def5eae0b29
Notes: Source: Scopus
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MSK Authors
  1. Britta Weigelt
    633 Weigelt
  2. Jorge Sergio Reis-Filho
    639 Reis-Filho
  3. Pier Selenica
    190 Selenica
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