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.
Schroeder
Joyce A
JA
Tumor Biology Program and Department of Biochemistry and Molecular Biology, Mayo Medical/Graduate School, Mayo Clinic Scottsdale, AZ 85259, USA.
Adriance
Melissa C
MC
Thompson
Melissa C
MC
Camenisch
Todd D
TD
Gendler
Sandra J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002472:Cell Transformation, Viral; D003094:Collagen; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005782:Gels; D006801:Humans; D008207:Lymphatic Metastasis; D046911:Macromolecular Substances; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D016596:Vinculin / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D005782:Gels; D046911:Macromolecular Substances; D018396:Mucin-1; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D015534:Trans-Activators; D051176:beta Catenin; D016596:Vinculin; D003094:Collagen