FOXK2 Transcription Factor Suppresses ERα-positive Breast Cancer Cell Growth Through Down-Regulating the Stability of ERα 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 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.

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear‐cell renal cell carcinoma

“…Moreover, the decreased FOXK2 mRNA levels predicted poor prognosis in patients with ccRCC, which was in accordance with the result of prognosis analysis on low FOXK2 expression in breast cancer. 18 Unlike previous studies, our results showed that in both FOXK2 knocked-down and overexpressed cells, no statistically significant changes were detected in the percentage of G0/G1 phases and S phase cells. We found that overexpression of FOXK2 inhibited the proliferation, migration and invasion of ccRCC cells, whereas knockdown of FOXK2 promoted these aspects.…”

“…Previous studies on breast cancer illustrated that knockdown of FOXK2 led to a significant decrease in the percentage of G0/ G1 phase cells and a increase in the percentage of S phase cells; 17 whereas overexpression of FOXK2 decreased the percentage of S phase cells. 18 Unlike previous studies, our results showed that in both FOXK2 knocked-down and overexpressed cells, no statistically significant changes were detected in the percentage of G0/G1 phases and S phase cells. These results agree with our previous finding that FOXK2 mRNA level has no correlation with ccRCC tumor size, which imply that other potential mechanisms may be involved in the tumor-suppressive function of FOXK2.…”

“…A previous study reported that FOXK2 expression was elevated in human colorectal cancer and is associated with intestinal tumorigenesis; 20 two other studies reported that FOXK2 was downregulated in breast cancer and suppressed the carcinogenesis of breast cancer. 17,18 However, the role that FOXK2 plays in ccRCC remains unknown. We demonstrated in our study that the mRNA and protein levels of FOXK2 were decreased in ccRCC tissues compared to those in adjacent non-tumor renal tissues.…”

“…10 Previous studies have shown that FOXK2 was involved in many molecular mechanisms, including starvationinduced autophagy, 11 cell adhesion and motility, 12,13 chromatin structure modification, [12][13][14] G/T-mismatch repair 15 and cell cycle regulation. 16 FOXK2 was also reported to play important roles in the carcinogenesis of breast cancer [17][18][19] and colorectal cancer. 20 Despite all these advances, the clinical relevance, biological function and molecular mechanism of FOXK2 in ccRCC remain unknown.…”

CCN5/WISP-2 restores ER-∝ in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen

“…For further confirmation of the involvement of CCN5 in activation and functional response of ER-α in BC cells, we determined whether blocking CCN5 activity by CCN5-specific antibody treatment reduces the proliferative effect of E2 or impede the effect of 4OH-Tam (4-hydroxy-tamoxifen) on MCF-7 cells. Consistent with previous works, 13 , 43 , 44 , 45 , 46 E2 (10 n m ) treatment for 48 h, significantly increased MCF-7 cell viability, and this effect of E2 was significantly blocked when cells were pre-treated for 48 h with CCN5-antibody (CCN5 Ab ) followed by concomitant treatment with E2 and CCN5 Ab ( Figure 7a ). Moreover, CCN5 Ab treatment also reduced the cytotoxic effect of 4OH-Tam (10 μ m ) in these cells but was unable to reduce downright.…”