MUC1-C Oncoprotein Induces TCF7L2 Transcription Factor Activation and Promotes Cyclin D1 Expression in Human Breast Cancer Cells

Abstract

Background: MUC1-C oncoprotein has been linked to ␤-catenin-dependent gene activation by mechanisms that are unclear. Results: MUC1-C binds directly to the TCF7L2 transcription factor and recruits ␤-catenin to the cyclin D1 promoter. Conclusion: MUC1-C induces cyclin D1 expression in breast cancer cells by activating TCF7L2-mediated transcription. Significance: Targeting MUC1-C function down-regulates cyclin D1 overexpression in breast cancer cells.

MUC1-C drives MYC in multiple myeloma

“…22,23 In concert with MUC1-C-mediated stabilization of b-catenin, silencing MUC1-C in MM cells is associated with decreases in b-catenin and slowing of growth. 24 These and other findings in breast cancer cells 25 have linked MUC1-C to activation of WNT/b-catenin signaling and the induction of WNT target genes. Significantly, the MUC1-C cytoplasmic domain also contains a CQC motif that is necessary for MUC1-C homodimerization and for localization of MUC1-C to the nucleus.…”

“…Previous work demonstrated that MUC1-C binds directly to TCF4 and forms a complex with TCF4 on the cyclin D1 promoter in breast cancer cells. 25 Moreover, MUC1-C promoted TCF4-mediated CCDN1 transcription by the recruitment of b-catenin. 25 In the present studies of MM cells, we found that MUC1-C occupies the MYC promoter in a complex with b-catenin/TCF4 (Figure 7).…”

“…25 Moreover, MUC1-C promoted TCF4-mediated CCDN1 transcription by the recruitment of b-catenin. 25 In the present studies of MM cells, we found that MUC1-C occupies the MYC promoter in a complex with b-catenin/TCF4 (Figure 7). Consistent with the finding that MUC1-C is of importance for b-catenin expression in MM cells, targeting MUC1-C was associated with marked decreases in b-catenin occupancy on the MYC promoter ( Figure 7).…”

MUC1 and metastatic cancer

“…As such, its interactions with MUC1 have been shown to promote transformation, primarily through MUC1-β-catenin protein complexes driving transcription of such genes as cyclin D1. 97 In addition, a study by Yuan et al demonstrated that the downregulation of MUC1 promoted E-cadherin/β-catenin complex formation, reduced nuclear β-catenin, upregulated both E-cadherin and β-catenin expression, and decreased invasive potential in PANC1 pancreatic cancer cells and MCF-7 breast cancer cells.…”

Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells

“…24,25 MUC1-C also localizes to the mitochondrial outer membrane, where it blocks loss of the mitochondrial transmembrane potential and activation of the intrinsic apoptotic pathway. 10 The mechanistic basis for such an anti-apoptotic effect resides, at least in part, in direct binding of MUC1-C to the BH3 domain of the pro-apoptotic BAX protein.…”