FOXK2 Transcription Factor Suppresses ERα-positive Breast Cancer Cell Growth Through Down-Regulating the Stability of ERα via mechanism involving BRCA1/BARD1

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