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Indexed by:期刊论文

Date of Publication:2015-03-05

Journal:SCIENTIFIC REPORTS

Included Journals:SCIE、PubMed

Volume:5

Page Number:8796

ISSN No.:2045-2322

Abstract:Estrogen receptors (ERs) are critical regulators of breast cancer development. Identification of molecules that regulate the function of ERs may facilitate the development of more effective breast cancer treatment strategies. In this study, we showed that the forkhead transcription factor FOXK2 interacted with ER alpha, and inhibited ER alpha-regulated transcriptional activities by enhancing the ubiquitin-mediated degradation of ER alpha. This process involved the interaction between FOXK2 and BRCA1/BARD1, the E3 ubiquitin ligase of ER alpha. FOXK2 interacted with BARD1 and acted as a scaffold protein for BRCA1/BARD1 and ER alpha, leading to enhanced degradation of ER alpha, which eventually accounted for its decreased transcriptional activity. Consistent with these observations, overexpression of FOXK2 inhibited the transcriptional activity of ER alpha, decreased the transcription of ER alpha target genes, and suppressed the proliferation of ER alpha-positive breast cancer cells. In contract, knockdown of FOXK2 in MCF-7 cells promoted cell proliferation. However, when ER alpha was also knocked down, knockdown of FOXK2 had no effect on cell proliferation. These findings suggested that FOXK2 might act as a negative regulator of ER alpha, and its association with both ER alpha and BRCA1/BARD1 could lead to the down-regulation of ER alpha transcriptional activity, effectively regulating the function of ER alpha.