Probing the Molecular Requirements for Breast Cancer Cell Motility




Dang, Tuyen Thi Thanh

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Invasion of breast cancer cells into the stroma is an early step in metastasis. How invasive ability is conferred in breast cancer cells is poorly understood. It has been shown that the tumor microenvironment can assist in the progression of cancer. The mechanism by which the microenvironment, specifically the mammary fibroblast, contributes to the invasion of breast cancer cells is unknown. To elucidate the function of mammary fibroblasts in breast cancer invasion, we co-cultured and co-injected breast cancer cells with mammary fibroblasts. We have found that mammary fibroblasts can induce invasion of motile basal-subtype breast cancer cells better than non-motile luminal subtype breast cancer cells. Based on these observations, the intrinsic motility of breast cancer cells was the determinate for invasion. To discover novel regulators of motility, we screened 879 distinct miRNAs using a wounding assay as a readout for migration. To prioritize, we determined which of the miRNAs inhibited migration and were expressed in non-motile breast cancer cells. This approach led us to focus on miR203a. We discovered that miR203a inhibits the expression of the transcription factor deltaNp63alpha, which leads to a decrease in cell migration. To determine how deltaNp63alpha controlled migration, we next determined which genes and miRNAs require deltaNp63alpha for expression. From these analyses, we discovered that deltaNp63alpha is required for the expression of miR205, the transcription factor Slug and the tyrosine kinase Axl. Additional functional analyses revealed that Slug, Axl and miR205 contributed to migration through their actions within parallel signaling pathways. Furthermore, using, an orthotropic xenograft model, we determined that deltaNp63alpha and Slug functionally contribute to the induction of collective invasion in vivo. Together, our results suggest a deltaNp63alpha dependent signaling through miR205, Axl, and Slug can lead to the induction of breast cancer invasion.

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