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

Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):E6600-E6609. doi: 10.1073/pnas.1612835113. Epub 2016 Oct 6.


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: FOXA1; breast cancer; endocrine resistance; estrogen receptor; transcriptional reprogramming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hepatocyte Nuclear Factor 3-alpha / genetics*
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Interleukin-8 / antagonists & inhibitors
  • Interleukin-8 / genetics*
  • Interleukin-8 / metabolism
  • Prognosis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Survival Analysis
  • Tamoxifen / therapeutic use
  • Transcriptome*


  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Interleukin-8
  • RNA, Small Interfering
  • Tamoxifen