FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

Xiaoyong Fu, Rinath Jeselsohn, Resel Pereira, Emporia F. Hollingsworth, Chad J. Creighton, Fugen Li, Martin Shea, Agostina Nardone, Carmine De Angelis, Laura M. Heiser, Pavana Anur, Nicholas Wang, Catherine S. Grasso, Paul T. Spellman, Obi L. Griffith, Anna Tsimelzon, Carolina Gutierrez, Shixia Huang, Dean P. Edwards, Meghana V. TrivediMothaffar F. Rimawi, Dolores Lopez-Terrada, Susan G. Hilsenbeck, Joe W. Gray, Myles Brown, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E6600-E6609
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number43
DOIs
StatePublished - Oct 25 2016

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Keywords

  • Breast cancer
  • Endocrine resistance
  • Estrogen receptor
  • FOXA1
  • Transcriptional reprogramming

ASJC Scopus subject areas

  • General

Cite this

Fu, X., Jeselsohn, R., Pereira, R., Hollingsworth, E. F., Creighton, C. J., Li, F., Shea, M., Nardone, A., De Angelis, C., Heiser, L. M., Anur, P., Wang, N., Grasso, C. S., Spellman, P. T., Griffith, O. L., Tsimelzon, A., Gutierrez, C., Huang, S., Edwards, D. P., ... Schiff, R. (2016). FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(43), E6600-E6609. https://doi.org/10.1073/pnas.1612835113