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

Fu, Xiaoyong ; Pereira, Resel ; De Angelis, Carmine ; Veeraraghavan, Jamunarani ; Nanda, Sarmistha ; Qin, Lanfang ; Cataldo, Maria L. ; Sethunath, Vidyalakshmi ; Mehravaran, Sepideh ; Gutierrez, Carolina ; Chamness, Gary C. ; Feng, Qin ; O’Malley, Bert W. ; Selenica, Pier ; Weigelt, Britta ; Reis-Filho, Jorge S. ; Cohen, Ofir ; Wagle, Nikhil ; Nardone, Agostina ; Jeselsohn, Rinath ; Brown, Myles ; Rimawi, Mothaffar F. ; Osborne, C. Kent ; Schiff, Rachel

Proceedings of the National Academy of Sciences - PNAS, 2019-12, Vol.116 (52), p.26823-26834 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer
Autor: Fu, Xiaoyong ; Pereira, Resel ; De Angelis, Carmine ; Veeraraghavan, Jamunarani ; Nanda, Sarmistha ; Qin, Lanfang ; Cataldo, Maria L. ; Sethunath, Vidyalakshmi ; Mehravaran, Sepideh ; Gutierrez, Carolina ; Chamness, Gary C. ; Feng, Qin ; O’Malley, Bert W. ; Selenica, Pier ; Weigelt, Britta ; Reis-Filho, Jorge S. ; Cohen, Ofir ; Wagle, Nikhil ; Nardone, Agostina ; Jeselsohn, Rinath ; Brown, Myles ; Rimawi, Mothaffar F. ; Osborne, C. Kent ; Schiff, Rachel
Assuntos: Biological Sciences ; Breast cancer ; Chromatin ; Clinical trials ; Embryogenesis ; Embryonic growth stage ; ErbB-2 protein ; Estrogen receptors ; Estrogens ; Forkhead protein ; Gene amplification ; Genomes ; Glioblastoma ; Hypoxia ; Hypoxia-inducible factors ; Metastases ; Metastasis ; Molecular modelling ; Mutation ; Transcription factors ; Up-regulation
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2019-12, Vol.116 (52), p.26823-26834
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Contributed by Myles Brown, November 6, 2019 (sent for review July 9, 2019; reviewed by Douglas Yee and Wilbert Zwart)
Author contributions: X.F., M.B., and R.S. designed research; X.F., R.P., C.D.A., J.V., S.N., L.Q., M.L.C., V.S., Q.F., O.C., N.W., A.N., and R.J. performed research; X.F. and R.S. supervised the study; B.W.O. and M.F.R. contributed new reagents/analytic tools; X.F., S.M., C.G., P.S., B.W., J.S.R.-F., O.C., N.W., and R.S. analyzed data; and X.F., G.C.C., R.J., M.B., C.K.O., and R.S. wrote the paper.
Reviewers: D.Y., University of Minnesota Medical Center; and W.Z., The Netherlands Cancer Institute.
Descrição: 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 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.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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

United States: National Academy of Sciences

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