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FOXA1 is a key determinant of estrogen receptor function and endocrine response | Nature Genetics
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Jason Carroll and colleagues report that the forkhead protein FOXA1 is an important determinant of estrogen receptor binding and show that expression of FOXA1 in non–breast cancer cells is sufficient to confer estrogen receptor binding and response to endocrine treatment. 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.
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nature portfolio permissions reprints privacy policy cancer research uk enhancer-driven lineage-specific transcription cambridge research institute advertising estrogen receptor-regulated transcription ccctc-binding factor confines nature 462 nature 406 nature social media endocrine-responsive breast cancer retinoic acid receptor-alpha p130–e2f4 complexes characteristic tamoxifen-resistant mcf-7 cells discover protein-dna interactions tamoxifen-dependent gene expression tissue-specific transcription author correspondence estrogen receptor alpha permissions personal data breast cancer cells breast cancer cells chromatin accessibility profiling enhanced estrogen receptor data protection breast cancer–correlation tamoxifen-resistant cells human breast tumours article type breast tumor subtypes estrogen receptor function androgen receptor interacts breast cancer res estrogen-er activity estrogen receptors alpha hutchison whampoa limited gene expression profiling endogenous gene expression privacy foxa1-bound enhancers upstream negative regulator competing financial interests chromosome-wide mapping tamoxifen-er activity genome-wide analysis cell cycle progression
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