The Cytoplasmic Domain of MUC1 Induces Hyperplasia in the Mammary Gland and Correlates with Nuclear Accumulation of β-Catenin

Abstract

MUC1 is an oncoprotein that is overexpressed in up to 90% of breast carcinomas. A previous in vitro study by our group demonstrated that the cytoplasmic domain of MUC1 (MUC1-CD), the minimal functional unit of MUC1, contributes to the malignant phenotype in cells by binding directly to β-catenin and protecting β-catenin from GSK3β-induced degradation. To understand the in vivo role of MUC1-CD in breast development, we generated a MUC1-CD transgenic mouse model under the control of the MMTV promoter in a C57BL/6J background, which is more resistant to breast tumor. We show that the expression of MUC1-CD in luminal epithelial cells of the mammary gland induced a hyperplasia phenotype characterized by the development of hyper-branching and extensive lobuloalveoli in transgenic mice. In addition to this hyperplasia, there was a marked increase in cellular proliferation in the mouse mammary gland. We further show that MUC1-CD induces nuclear localization of β-catenin, which is associated with a significant increase of β-catenin activity, as shown by the elevated expression of cyclin D1 and c-Myc in MMTV-MUC1-CD mice. Consistent with this finding, we observed that overexpression of MUC1-C is associated with β-catenin nuclear localization in tumor tissues and increased expression of Cyclin D1 and c-Myc in breast carcinoma specimens. Collectively, our data indicate a critical role for MUC1-CD in the development of mammary gland preneoplasia and tumorigenesis, suggesting MUC1-CD as a potential target for the diagnosis and chemoprevention of human breast cancer.

MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches

“…In support of this model, expression of the MUC1-C cytoplasmic domain in the mammary glands of transgenic mice results in marked hyperplasia, increased abundance of β-catenin in the nucleus and induced activation of the Wnt target genes encoding cyclin D1 and c-Myc (70). …”

MUC1-C drives MYC in multiple myeloma

“…22 Stabilization of b-catenin by MUC1-C has been confirmed in other studies. 34,[40][41][42][43] In this context, downregulation of MUC1-C in RPMI8226/CRISPR cells was associated with decreased b-catenin levels, but had little effect on the expression of GSK3b (Figure 2A). We also found that b-catenin expression is decreased in U266/CRISPR cells ( Figure 2B).…”

Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer

“…Overexpression of MUC1 promotes breast cancer development [2] and overexpression of its intracellular domain leads to mammary gland hyperplasia in mouse models [16]. Several in vitro studies have shown the role of MUC1 in influencing cellular processes like regulation of cell polarity, transcriptional control, inhibition of apoptosis and blocking of death-signals by interaction with intracellular signaling pathways like β-Catenin, EGFR, Wnt and NFκB signaling [1,17].…”