MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion.
MUC1 is aberrantly expressed in greater than 90% of all breast carcinomas, yet its function as a tumor antigen is not fully understood. Recently, studies have shown that MUC1 interacts with beta-catenin, erbB receptors, src, GSK-3beta and protein kinase Cdelta, possibly in a complex that promotes the disassembly of adherens ... junctions and the invasion of cells. Here we show that the deletion of Muc1 expression from MMTV-Wnt-1 transgenic mice results in a significant increase in the time to mammary gland tumor onset. Analysis of MMTV-Wnt-1 tumors on a wild-type Muc1 background shows a tumor-specific complex formation between Muc1 and beta-catenin that can be observed in both the membrane and the cytoplasm of transformed epithelium. Analysis of primary human adenocarcinomas revealed that this MUC1/beta-catenin interaction occurs in both primary and metastatic tumors, but is dramatically increased in metastatic lesions. Addition of MUC1-cytoplasmic domain peptides to the invasive MDA-MB-468 and MDA-MB-231 cell lines increases their invasive capability, and these peptides colocalize with both beta-catenin and the focal adhesion protein vinculin, primarily at sites of membrane invasion into a collagen matrix. These data indicate a potential mechanism for MUC1 promotion of invasive tumorigenesis in the breast through the modulation of beta-catenin localization and subsequent cytoskeletal dynamics.
Mesh Terms:
Amino Acid Sequence, Animals, Breast Neoplasms, Carcinoma, Ductal, Breast, Cell Membrane, Cell Transformation, Viral, Collagen, Cytoplasm, Cytoskeletal Proteins, Cytoskeleton, Female, Gels, Humans, Lymphatic Metastasis, Macromolecular Substances, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Molecular Sequence Data, Mucin-1, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Proteins, Peptide Fragments, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Tertiary, Trans-Activators, Tumor Cells, Cultured, Vinculin, beta Catenin
Amino Acid Sequence, Animals, Breast Neoplasms, Carcinoma, Ductal, Breast, Cell Membrane, Cell Transformation, Viral, Collagen, Cytoplasm, Cytoskeletal Proteins, Cytoskeleton, Female, Gels, Humans, Lymphatic Metastasis, Macromolecular Substances, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Molecular Sequence Data, Mucin-1, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Proteins, Peptide Fragments, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Tertiary, Trans-Activators, Tumor Cells, Cultured, Vinculin, beta Catenin
Oncogene
Date: Mar. 06, 2003
PubMed ID: 12618757
View in: Pubmed Google Scholar
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