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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 ? (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.

SUBMITTER: Fu X

PROVIDER: S-EPMC5087040 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Fu Xiaoyong X Jeselsohn Rinath R Pereira Resel R Hollingsworth Emporia F EF Creighton Chad J CJ Li Fugen F Shea Martin M Nardone Agostina A De Angelis Carmine C Heiser Laura M LM Anur Pavana P Wang Nicholas N Grasso Catherine S CS Spellman Paul T PT Griffith Obi L OL Tsimelzon Anna A Gutierrez Carolina C Huang Shixia S Edwards Dean P DP Trivedi Meghana V MV Rimawi Mothaffar F MF Lopez-Terrada Dolores D Hilsenbeck Susan G SG Gray Joe W JW Brown Myles M Osborne C Kent CK Schiff Rachel R

Proceedings of the National Academy of Sciences of the United States of America 20161006 43

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 profil ...[more]

PMID: 27791031

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Project description:Breast cancer is one of the most common malignant cancers affecting females. Estrogen receptor (ER)-positive breast cancer is responsive to endocrine therapy. Although current therapies offer favorable prospects for improving survival, the development of resistance remains a severe problem. In this study, we explored the resistance mechanisms of ER-positive breast cancer to neoadjuvant endocrine therapy. Microarray data of GSE87411 contained 109 pairs of samples from Z1031 trial, including untreated samples and post-treated samples with neoadjuvant aromatase inhibitor (AI) therapy. The differentially expressed genes (DEGs) were obtained from two different comparisons: untreated samples versus post-treated samples with AIs, and post-treated samples sensitive versus resistant to AIs. Multiple bioinformatic methods were applied to evaluate biological function, protein-protein network and potential binding between target protein and aromatase inhibitor. Then, regulation of gene expression, DNA methylation and clinicopathological factors of breast cancer were further analyzed with TCGA data. From GSE87411 dataset, 30 overlapped DEGs were identified. Cell division was found to be the main function of overlapped DEGs by functional enrichment and gene ontology (GO) analysis. RAD51 recombinase (RAD51), a key protein of homologous recombination, was detected to interact with BReast CAncer genes 2 (BRCA2). Moreover, according to the docking simulation, RAD51 might potentially bind to AIs. Overexpressed RAD51 was associated with hypermethylation of BRCA2, resistance to AIs and poor overall survival of patients with ER-positive breast cancer. Furthermore, RAD51 was found to be a better indicator than MKI67 for predicting resistance in neoadjuvant setting. The results indicated that methylation of BRCA2 led to incomplete suppression on RAD51, which caused an increased expression of RAD51, subsequently AI-resistance and poor prognosis in ER-positive breast cancer. RAD51 could be a new candidate used as a predicative marker and therapeutic target in neoadjuvant endocrine treatment.

Dataset Information

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

Publications

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

Similar Datasets

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