4.8 Article

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

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612835113

Keywords

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

Funding

  1. Department of Defense Breakthrough Award [W81XWH-14-1-0326]
  2. Breast Cancer Research Foundation
  3. Stand Up to Cancer Translational Grant [SU2C-AACR-DT0409]
  4. NIH Breast Cancer Specialized Programs of Research Excellence [P50CA058183, P50CA186784]
  5. NIH Cancer Center [P30CA125123]
  6. Susan G. Komen for the Cure Foundation Promise [PG12221410, SAC110012]
  7. Cancer Prevention Research Institute of Texas [RP120092]
  8. NIH [P30CA125123, P30AI036211, S10RR024574]
  9. Proteomics & Metabolomics Core Facility
  10. Cytometry and Cell Sorting Core at Baylor College of Medicine

Ask authors/readers for more resources

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor alpha(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 in-hibits 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.

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