Mechanisms of MUC1/ICAM-1 signalling in breast cancer metastasis

  • Author / Creator
    Bernier, Ashlyn
  • Breast cancer is the second leading cause of cancer death in Canadian women. In these patients, mortality is due to metastasis of cancer cells from the breast to distant organs, resulting in impairment of function. To metastasize, cells must move through the stroma of the breast, enter the circulation, survive transit, exit the circulation, and form a secondary tumor. A critical component of this metastatic cascade is cancer cell motility. It is not fully understood how breast cancer cells gain the ability to move or what signaling pathways mediate these events, and identification of critical components of these pathways would represent potential targets for anti-metastatic therapies. The MUC1 glycoprotein is expressed on the apical membrane of normal breast epithelia. In many human breast carcinomas, MUC1 is overexpressed and loses apical polarization, events that correlate with increased metastasis. The contribution of MUC1 overexpression to increased metastasis is not completely understood, with the majority of studies attributing an anti-adhesive role to MUC1. Several critical steps of the metastatic cascade require cell adhesion, and it has been reported that MUC1 is a ligand for ICAM-1, which is expressed throughout the migratory tract of a metastasizing breast cancer cell. It was subsequently reported that MUC1/ICAM-1 binding initiates calcium oscillations, cytoskeletal reorganization, and cell migration, suggesting that binding could be important in metastasis. Here, we investigate the mechanism of MUC1/ICAM-1 binding induced signaling. We show that Src kinase is a critical component of the MUC1/ICAM-1 signalling axis, and that MUC1 forms constitutive dimers which are required for Src recruitment and ICAM-1 binding induced signaling. We show that MUC1 dimers are not covalently linked and do not require cytoplasmic domain cysteine residues, contrary to other reports. We show that MUC1 extracellular domain shedding is not required for dimerization, Src recruitment, or ICAM-1 binding induced calcium oscillations, although it is required for migration. Lastly, we show that autoproteolytic cleavage of MUC1 is not required for normal function. These results reveal information on the mechanism of MUC1/ICAM-1 signalling, which can be used to identify novel targets and combinational strategies for anti-metastatic therapy in breast cancer.

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    Doctor of Philosophy
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