Regulation of Snail in breast cancer progression and metastasis

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DESCRIPTION (provided by applicant): Approximately 90% of breast cancer deaths are caused by metastasis, and the median survival time for patients with metastatic breast cancer is approximately 2 years. Therefore, an understanding of the mechanisms at work in the initiation and progression of metastasis is important for prevention and treatment of breast cancer. Our long-term goal is to reduce the incidence of breast cancer metastasis by gaining an understanding of the molecular mechanism underlying the initial step of breast cancer metastasis. As the master switch for epithelial-mesenchymal transition (EMT) and the initial step of metastasis, Snail plays a critical role in the initiation and progression of metastasis. Overexpression of Snail correlates with tumor grade and nodal metastasis of breast cancer, but the mechanism remains unclear. We recently demonstrated that the activity of Snail is regulated mainly by its protein stability and cellular location. Using an unbiased approach-tandem array purification (TAP) coupled with mass spectrometry analysis, we identified the interaction of Snail with EPLINb (Epithelial Protein Lost in Neoplasm). We found that downregulation of EPLINP correlated with the upregulation of Snail in breast cancer cell lines and metastatic breast cancer specimens. We further demonstrated that expression of EPLINb induces degradation of Snail and relieves suppression of the E-cadherin promoter mediated by Snail. The central hypothesis of our proposal is that EPLINb functions as a negative regulator for Snail and that loss of EPLINb in breast cancer induces the stabilization and nuclear localization of Snail, thus triggering breast cancer progression and metastasis. The objective of this proposal is to decipher the functional regulation of Snail by EPLINb in breast cancer and explore the prognostic value of EPLINb and Snail as markers of metastasis in breast cancer. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to delineate the regions on Snail and EPLINb required for their association; (2) to determine whether the loss of EPLINb enhances the stabilization of Snail; and (3) to define the functional regulation of Snail and EPLINb in mouse and human breast cancer. Our proposal is innovative and significant to public health because knowledge gained from this study will expand the understanding of the initiation and progression of metastasis and holds great promise for novel interventions for preventing and treating breast cancer.