FOXK2 transcription factor suppresses ER?-positive breast cancer cell growth through down-regulating the stability of ER? via mechanism involving BRCA1/BARD1.

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?, and inhibited ER?-regulated transcriptional activities by enhancing the ubiquitin-mediated degradation of ER?. This process involved the interaction between FOXK2 and BRCA1/BARD1, the E3 ubiquitin ligase of ER?. FOXK2 interacted with BARD1 and acted as a scaffold protein for BRCA1/BARD1 and ER?, leading to enhanced degradation of ER?, which eventually accounted for its decreased transcriptional activity. Consistent with these observations, overexpression of FOXK2 inhibited the transcriptional activity of ER?, decreased the transcription of ER? target genes, and suppressed the proliferation of ER?-positive breast cancer cells. In contract, knockdown of FOXK2 in MCF-7 cells promoted cell proliferation. However, when ER? 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?, and its association with both ER? and BRCA1/BARD1 could lead to the down-regulation of ER? transcriptional activity, effectively regulating the function of ER?.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC4350111 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other