TY - JOUR
T1 - FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer
AU - Fu, Xiaoyong
AU - Pereira, Resel
AU - De Angelis, Carmine
AU - Veeraraghavan, Jamunarani
AU - Nanda, Sarmistha
AU - Qin, Lanfang
AU - Cataldo, Maria L.
AU - Sethunath, Vidyalakshmi
AU - Mehravaran, Sepideh
AU - Gutierrez, Carolina
AU - Chamness, Gary C.
AU - Feng, Qin
AU - O'Malley, Bert W.
AU - Selenica, Pier
AU - Weigelt, Britta
AU - Reis-Filho, Jorge S.
AU - Cohen, Ofir
AU - Wagle, Nikhil
AU - Nardone, Agostina
AU - Jeselsohn, Rinath
AU - Brown, Myles
AU - Rimawi, Mothaffar F.
AU - Osborne, C. Kent
AU - Schiff, Rachel
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Rena Mao and Joy Guo for performing immunohistochemistry; and Fuli Jia, Myra Costello, and Dr. Kimberley Holloway for performing the reverse-phase protein array assays. This work was supported by the Department of Defense Breakthrough Award W81XWH-14-1-0326 (to X.F.); the Breast Cancer Research Foundation BCRF 17-143 and 18-145 (to R.S. and C.K.O.); Stand Up to Cancer Translational Grant SU2C-AACR-DT0409 (to R.S. and C.K.O.); National Institutes of Health (NIH) Breast Cancer Specialized Programs of Research Excellence Grants P50-CA058183 and CA186784 (to C.K.O., R.S., and M.F.R.), and P50-CA168504 (to N.W.); NIH/National Cancer Institute Cancer Center Support Grants P30-CA125123 and CA008748 (to C.K.O.), and P30-CA008748 (to J.S.R.-F. and B.W.); NIH Grant R61AI133697 (to Q.F.); Susan G. Komen Grant CCR15333343 (to N.W.); The V Foundation (N.W.); The Breast Cancer Alliance (N.W.); and The Cancer Couch Foundation (N.W.). This work was also supported by the Cancer Prevention & Research Institute of Texas (CPRIT) Grant RP190398 (to R.S. and X.F.); CPRIT Proteomics & Metabo-lomics Core Facility Support Award RP170005; and National Cancer Institute Cancer Center Support Grant to Antibody-based Proteomics Core/ Shared Resource P30CA125123.
Funding Information:
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. Competing interest statement: C.K.O. is a consultant/advisory board member for AstraZeneca, GlaxoSmithKline, Pfizer, Puma Biotechnologies, and Tolmar, and on the Data Monitoring Committee for Eli Lilly. R.S. has received research support from AstraZeneca, GlaxoSmithKline, Gilead, and Puma Biotechnology, served as a consultant to Eli Lilly, and is a consultant/advisory board member for MacroGenics. J.S.R.-F. has received personal/consultancy fees from Goldman Sachs, VolitionRx, Page.AI, Grail, Roche, Invicro, and Ventana Medical Systems, outside the submitted work. N.W. has received research support from Novartis and Puma Biotechnology, consults with Novartis, consults with and holds stock from Foundation Medicine, and is a consultant/advisor of Eli Lilly. R.J. has received research funding from Pfizer. M.B. receives sponsored research support from Novartis, serves on the Scientific Advisory Board of Kronos Bio and is a consultant to H3 Biomedicine. M.F.R. has received research support from GlaxoSmithKline and Pfizer, and consults with Genentech, Novartis, Daiichi, and MacroGenics. The remaining authors declare that they have no competing interests. Published under the PNAS license.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/12/26
Y1 - 2019/12/26
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Endocrine resistance
KW - Enhancer/transcriptional reprogramming
KW - FOXA1
KW - Metastasis
UR - http://www.scopus.com/inward/record.url?scp=85077266207&partnerID=8YFLogxK
U2 - 10.1073/pnas.1911584116
DO - 10.1073/pnas.1911584116
M3 - Article
C2 - 31826955
AN - SCOPUS:85077266207
SN - 0027-8424
VL - 116
SP - 26823
EP - 26834
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -