Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):E6600-E6609. Epub 2016 Oct 6.

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

Author information

1
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
2
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
3
Department of Pathology, Baylor College of Medicine, Houston, TX 77030.
4
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
5
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
6
Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239.
7
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239.
8
McDonnell Genome Institute, Washington University, St. Louis, MO 63108.
9
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
10
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Pathology, Baylor College of Medicine, Houston, TX 77030.
11
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX 77204; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204.
12
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
13
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030; rschiff@bcm.edu.

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:

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

PMID:
27791031
PMCID:
PMC5087040
DOI:
10.1073/pnas.1612835113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center