The Role of the Rab Coupling Protein in ErbB2-Driven Mammary Tumorigenesis and Metastasis

During the Year-1 we characterized the role of RCP in ErbB2-driven breast cancer model. To directly evaluate the RCP in ErbB2 mammary tumorigenesis, we have derived transgenic mice that inducibly express RCP in the mammary epithelium and interbreed these mice with separate strain expressing an MMTV activated ErbB2 transgene. Induction of RCP expression in the ErbB2-driven model results in a tumor onset delay in addition to a drastic defect in metastasis formation. Furthermore, elevated RCP expression promotes a significant decrease in cell proliferation that is associated with a Senescence Associated to Heterochromatin Foci cellular senescence phenotype. In addition, using in vitro 3D-cell culture model of ErbB2 positive breast cancer, we showed that RCP is essential to the maintenance of adherens junctions by regulating E-cadherin endocytosis. Conversely depletion of RCP in ErbB2 positive cell lines leads to a significant increase in the number of lung metastases. Consistent with the importance of RCP as negative regulator of ErbB2 positive breast cancer progression, gene expression profile analysis of tumor banks of human breast tumors showed that the expression of RCP is inversely correlated with ErbB2 levels. Overall, ether, these observations argue that RCP acts as a tumor suppressor in ErbB2-driven breast cancer progression.
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