title: FOXA1 is a key determinant of estrogen receptor function and endocrine response.
abstract: Estrogen receptor-α (ER) is the key feature of most breast cancers and binding of ER to the genome correlates with expression of the Forkhead protein FOXA1 (also called HNF3α). Here we show that FOXA1 is a key determinant that can influence differential interactions between ER and chromatin. Almost all ER-chromatin interactions and gene expression changes depended on the presence of FOXA1 and FOXA1 influenced genome-wide chromatin accessibility. Furthermore, we found that CTCF was an upstream negative regulator of FOXA1-chromatin interactions. In estrogen-responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity was absolute; in tamoxifen-resistant cells, ER binding was independent of ligand but depended on FOXA1. Expression of FOXA1 in non-breast cancer cells can alter ER binding and function. As such, FOXA1 is a major determinant of estrogen-ER activity and endocrine response in breast cancer cells.
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Antoni
authors.initials: A
authors.lastname: Hurtado
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Holmes
authors.forename: Caryn S
authors.initials: CS
authors.lastname: Ross-Innes
authors.forename: Dominic
authors.initials: D
authors.lastname: Schmidt
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D014162:Transfection
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha