@article{39c58618140d40c491f3dde10d17fd8c,
title = "FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer",
abstract = "Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.",
keywords = "Breast cancer, Endocrine resistance, Estrogen receptor, FOXA1, Transcriptional reprogramming",
author = "Xiaoyong Fu and Rinath Jeselsohn and Resel Pereira and Hollingsworth, {Emporia F.} and Creighton, {Chad J.} and Fugen Li and Martin Shea and Agostina Nardone and {De Angelis}, Carmine and Heiser, {Laura M.} and Pavana Anur and Nicholas Wang and Grasso, {Catherine S.} and Spellman, {Paul T.} and Griffith, {Obi L.} and Anna Tsimelzon and Carolina Gutierrez and Shixia Huang and Edwards, {Dean P.} and Trivedi, {Meghana V.} and Rimawi, {Mothaffar F.} and Dolores Lopez-Terrada and Hilsenbeck, {Susan G.} and Gray, {Joe W.} and Myles Brown and Osborne, {C. Kent} and Rachel Schiff",
note = "Funding Information: We thank Drs. Robert Nicholson and Julia Gee for providing the paired MCF7RN-P and TamR cell line model; Dr. Mathieu Lupien for sharing ER ChIP-chip data; Rena Mao and Joy Guo for performing IHC; Fuli Jia, Myra Costello, and Dr. Kimberley Holloway for performing RPPA assay; Drs. Kimal Rajapakshe, Cristian Coarfa, and Qianxing Mo for RPPA data processing; and Dr. Gary Chamness for reading and reviewing this manuscript. This work was supported by Department of Defense Breakthrough Award W81XWH-14-1-0326 (to X.F.), the Breast Cancer Research Foundation (R.S. and C.K.O.), Stand Up to Cancer Translational Grant SU2CAACR-DT0409 (to R.S., C.K.O., and J.W.G.), NIH Breast Cancer Specialized Programs of Research Excellence Grants P50CA058183 and P50CA186784 (to C.K.O. and R.S.), NIH Cancer Center Grant P30CA125123 (to C.K.O.), and Susan G. Komen for the Cure Foundation Promise Grants PG12221410 (to C.K.O. and R.S.) and SAC110012 (to J.W. G.). This work was supported by Proteomics & Metabolomics Core Facility with funding from Cancer Prevention Research Institute of Texas Grant RP120092 (to S.H. and D.P.E.) and Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from NIH Grants P30AI036211, P30CA125123, and S10RR024574 and the expert assistance of Joel M. Sederstrom.",
year = "2016",
month = oct,
day = "25",
doi = "10.1073/pnas.1612835113",
language = "English (US)",
volume = "113",
pages = "E6600--E6609",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "43",
}