A pilot study to investigate in vivo Miro1 deletion in breast cancer tumorigenesis

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PROJECT SUMMARY Metastatic breast cancer has no cure and therefore biomarkers of metastatic potential and new targets for therapeutic intervention are required. Mitochondria are trafficked to the leading edge of cells to support cell migration and metastasis. The proper positioning of mitochondria is required to regulate local levels of mitochondrial derived molecules to control subcellular signaling. Knockout/down of Miro1, the primary mitochondrial adapter required for subcellular trafficking of mitochondria, restricts mitochondria perinuclear and compromises cell migration in normal and metastatic breast cancer cells. Furthermore, levels of mitochondrial derived molecules are reduced in the cell periphery when mitochondria are restricted perinuclear. As high Miro1 expression is correlated with poor prognosis in breast cancer patients, investigating the role of Miro1 in tumorigenesis is a new avenue for the identification of biomarkers of metastatic potential and new targets for therapeutic intervention. Our preliminary studies indicate that Miro1-mediated mitochondrial positioning supports cell migration and metastasis in breast cancer. To expand upon these in vitro assays, we propose the use of a novel breast cancer mouse model to investigate Miro1 and mitochondrial dynamics in tumorigenesis. In Specific Aim 1 we will translate our preliminary findings in cells into a novel mouse model of breast cancer in which we will investigate the role of Miro1 in the initiation, progression and metastasis of breast cancer. We will evaluate standard markers of breast cancer progression and changes in gene expression patterns dependent on Miro1 expression. This pilot study will highlight the role of Miro1-mediated mitochondrial positioning in supporting tumorigenesis and metastasis. These studies will identify relevant gene and protein expression signatures and provide rationale for investigating these pathways as potential biomarkers of disease progression and avenues for therapeutic intervention.