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FOXA1 Upregulation Promotes Enhancer and Transcriptional Reprogramming in Endocrine-Resistant Breast Cancer

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FOXA1 Upregulation Promotes Enhancer and Transcriptional Reprogramming in Endocrine-Resistant Breast Cancer FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer Xiaoyong Fua,b,c,1, Resel Pereiraa,b,c, Carmine De Angelisa,b,d, Jamunarani Veeraraghavana,b,d, Sarmistha Nandaa,b,d, Lanfang Qina,b,d, Maria L. Cataldoa,b,d, Vidyalakshmi Sethunatha,b,d, Sepideh Mehravaranb,e, Carolina Gutierrezb,e, Gary C. Chamnessa,b,d, Qin Fengf, Bert W. O’Malleyb,c, Pier Selenicag, Britta Weigeltg, Jorge S. Reis-Filhog, Ofir Cohenh,i,j, Nikhil Wagleh,i,j, Agostina Nardonek, Rinath Jeselsohnh,k, Myles Brownh,k,1, Mothaffar F. Rimawia,b,d, C. Kent Osbornea,b,c,d, and Rachel Schiffa,b,c,d,1 aLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; bDan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030; cDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; dDepartment of Medicine, Baylor College of Medicine, Houston, TX 77030; eDepartment of Pathology, Baylor College of Medicine, Houston, TX 77030; fDepartment of Biology and Biochemistry, University of Houston, Houston, TX 77204; gDepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065; hDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210; iCenter for Cancer Precision Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210; jBroad Institute of MIT and Harvard, Cambridge, MA 02142; and kCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210 Contributed by Myles Brown, November 6, 2019 (sent for review July 9, 2019; reviewed by Douglas Yee and Wilbert Zwart) Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic Significance transcription factors. Hyperactive FOXA1 signaling due to gene am- plification or overexpression has been reported in estrogen receptor- FOXA1 augmentation, including by genetic aberrations, drives + + positive (ER ) endocrine-resistant metastatic breast cancer. However, aggressive phenotypes of estrogen receptor-positive (ER ) the molecular mechanisms by which FOXA1 up-regulation promotes breast cancer (BC). Here, we show that FOXA1 upregulation in- these processes and the key downstream targets of the FOXA1 on- duces genome-wide enhancer reprogramming and adopts a MEDICAL SCIENCES cogenic network remain elusive. Here, we demonstrate that FOXA1 superenhancer mechanism to activate the master transcription + overexpression in ER breast cancer cells drives genome-wide en- factor HIF-2α and a prometastatic transcriptional program. The hancer reprogramming to activate prometastatic transcriptional hyperactive FOXA1/HIF-2α transcriptional axis is observed to be + programs. Up-regulated FOXA1 employs superenhancers (SEs) to largely nonconcurrent with the ESR1 mutations in clinical ER / − synchronize transcriptional reprogramming in endocrine-resistant HER2 metastatic BC datasets, suggesting different mechanisms breast cancer cells, reflecting an early embryonic development pro- of resistance. Furthermore, a selective HIF-2α inhibitor, currently cess. We identify the hypoxia-inducible transcription factor hypoxia- in clinical trials for advanced renal cell carcinoma and glioblas- inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, toma, inhibits the clonogenicity, migration, and invasion of mediating the impact of high FOXA1 in activating prometastatic endocrine-resistant BC cells. These findings demonstrate the role gene sets and pathways associated with poor clinical outcome. Using of FOXA1 upregulation in enhancer reprogramming and a clinical ER+/HER2− metastatic breast cancer datasets, we show that therapeutic approach of targeting deregulated transcriptional the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcur- programs to circumvent endocrine-resistant metastatic BC. rent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demon- Author contributions: X.F., M.B., and R.S. designed research; X.F., R.P., C.D.A., J.V., S.N., α 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. super- strate the selective efficacy of an HIF-2 antagonist, currently in vised the study; B.W.O. and M.F.R. contributed new reagents/analytic tools; X.F., S.M., clinical trials for advanced kidney cancer and recurrent glioblastoma, 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., in reducing the clonogenicity, migration, and invasion of endocrine- C.K.O., and R.S. wrote the paper. resistant breast cancer cells expressing high FOXA1. Our study has Reviewers: D.Y., University of Minnesota Medical Center; and W.Z., The Netherlands uncovered high FOXA1-induced enhancer reprogramming and HIF- Cancer Institute. 2α–dependent transcriptional programs as vulnerable targets for Competing interest statement: C.K.O. is a consultant/advisory board member for AstraZeneca, treating endocrine-resistant and metastatic breast cancer. GlaxoSmithKline, Pfizer, Puma Biotechnologies, and Tolmar, and on the Data Monitor- ing 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 breast cancer | endocrine resistance | FOXA1 | enhancer/transcriptional a consultant/advisory board member for MacroGenics. J.S.R.-F. has received personal/consul- reprogramming | metastasis tancy 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 esistance to endocrine therapy in estrogen receptor-positive Foundation Medicine, and is a consultant/advisor of Eli Lilly. R.J. has received research fund- + R(ER ) breast cancer (BC) is common, and leads to poor ing from Pfizer. M.B. receives sponsored research support from Novartis, serves on the Sci- entific Advisory Board of Kronos Bio and is a consultant to H3 Biomedicine. M.F.R. has clinical outcome (1). It has been shown that when ER is inhibited, received research support from GlaxoSmithKline and Pfizer, and consults with Genentech, tumors may activate growth factor receptor (GFR)-related path- Novartis, Daiichi, and MacroGenics. The remaining authors declare that they have no ways to drive endocrine resistance (2–4). However, with the competing interests. exception of the mammalian target of rapamycin inhibitor Published under the PNAS license. everolimus (5), CDK4/6 inhibitors (6), and the PI3K-α isoform- Data deposition: The data reported in this paper have been deposited in the Gene Ex- specific inhibitor alpelisib (7), results of clinical trials using kinase pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE124656). inhibitors targeting the GFR-related pathways, especially as single 1To whom correspondence may be addressed. Email: [email protected], myles_brown@ agents, are mostly disappointing. Recurrent ESR1 mutations, ob- dfci.harvard.edu, or [email protected]. ∼ + served in 30% of ER metastatic BCs (MBCs), especially those This article contains supporting information online at https://www.pnas.org/lookup/suppl/ treated with aromatase inhibitors (AIs), are recognized as an doi:10.1073/pnas.1911584116/-/DCSupplemental. important mechanism of endocrine resistance, but only in a subset www.pnas.org/cgi/doi/10.1073/pnas.1911584116 PNAS Latest Articles | 1of12 Downloaded by guest on September 24, 2021 + of ER tumors (8). Other molecular mechanisms underlying endo- thereby promoting tumor progression. Upon FOXA1 induction, crine resistance in the metastatic disease are still poorly understood. FOXA1 chromatin-immunoprecipitation and sequencing (ChIP- FOXA1 is a transcription factor (TF) of the Forkhead box seq) revealed a substantial increase of 60,543 FOXA1 binding (FOX) protein family. It functions as a pioneer factor that binds sites, while 12,721 preexisting sites remained but 15,210 were lost to condensed chromatin to facilitate subsequent binding of ER (Fig. 1A). The increased FOXA1 binding mainly occurred at (9) and other lineage-specific TFs. By characterizing multiple intronic and intergenic regions (SI Appendix,Fig.S1B), similar to endocrine-resistant preclinical BC cell models, we have recently that observed for endogenous FOXA1 binding in both MCF7-P shown that high FOXA1 (H-FOXA1), via gene amplifica- and TamR cells (10, 17, 22). tion and overexpression (OE), plays a key role in promoting To determine how the enhancer landscape evolves upon endocrine-resistant cell growth and invasiveness by reprogram- H-FOXA1 induction, we next performed ChIP-seq of the two ming the ER-dependent transcriptome (10). In addition, several + enhancer marks, H3K27 acetylation (ac) and H3K4me1. Dif- clinical sequencing studies of ER disease reported that about ferential peak analysis identified more regions with increased 6% of primary and 10% of metastatic tumors harbor FOXA1 (GAIN) than with decreased (LOSS) H3K27ac (5,010 vs. 1,722) genetic aberrations, including gene amplification and missense (Fig. 1B). Additionally, substantially more GAIN than LOSS mutations associated with FOXA1 activation (11, 12). A recent regions of H3K4me1 (7,516 vs. 68) were identified in +Dox vs. deep-sequencing study of the
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