title: 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.
authors.affiliation: Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Haiying
authors.initials: H
authors.lastname: Yi
authors.forename: Yixin
authors.initials: Y
authors.lastname: Yao
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liao
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Xie
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yan
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Shunyuan
authors.initials: S
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Kuang
authors.forename: Mingmin
authors.initials: M
authors.lastname: Gu
authors.forename: Jian
authors.initials: J
authors.lastname: Fei
authors.forename: Zhugang
authors.initials: Z
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D006965:Hyperplasia / Q000473:pathology*; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: D018396:Mucin-1