The SWI/SNF chromatin remodeling subunit BAF57 is a critical regulator of estrogen receptor function in breast cancer cells.
Estrogen receptors (ERs) play critical roles in both normal mammary gland development and in the formation and progression of breast tumors, constituting a major therapeutic target for breast cancer treatment. We have previously described that ER transcriptional activity is potentiated by BAF57, a core subunit of the mammalian SWI/SNF chromatin remodeling complex. Here we provide evidence demonstrating an important role for BAF57 as regulator of ER functions in breast cancer cells. Different experimental manipulations leading to the abrogation of BAF57 expression and/or function severely reduced the expression of various endogenous ER target genes and blocked estrogen-stimulated proliferation in ZR-75-1 breast cancer cells. Moreover, using a structure-function analysis, we have defined the protein domains required for the functional interaction between ERalpha and BAF57, including a key region within the hinge of ERalpha that is essential for BAF57 recruitment and its function on ER-mediated transcription. Interestingly, we found that BAF57 is an ER subtype-selective modulator that specifically regulates ERalpha-mediated transcription. Taken together, our results suggest that targeting BAF57 could represent a new way to effectively inhibit the action of ERalpha.
García-Pedrero
Juana M
JM
Institute of Reproductive and Developmental Biology, Imperial College London, London W12 ONN, United Kingdom.
Kiskinis
Evangelos
E
Parker
Malcolm G
MG
Belandia
Borja
B
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C504738:SMARCE1 protein, human