The causes and consequences of regulation of Deltanp63alpha in mammary and breast cancer stem cells.

摘要

Despite the array of targeted therapeutics that currently exist to combat breast cancer, disease progression leading to metastasis, and tumor recurrence still remains a significant clinical challenge. Efforts to identify novel pathways and mechanisms that mediate metastasis or recurrence has focused on a small subset of cells in the mammary gland and breast tumors known as mammary stem cells and breast cancer stem cells respectively. Akin to normal mammary stem cells, breast cancer stem cells also possess the ability to retain self-renewing capabilities, a prolonged life span and developmental potency, identifying them as a critical component of therapeutic resistance and metastatic development. The pathways and mechanisms that are utilized to mediate such phenotypes in these cell populations are poorly understood, and elucidation of such mechanisms may lead to the development of more effective therapeutic strategies. The predominant isoform of the TP63 gene, DeltaNP63alpha is implicated in the self-renewal and preservation of epithelial stem cells, including mammary stem cells. However, the mechanisms by which this regulation is achieved, and DeltaNP63alpha's role in cancer stem cells and metastasis remains poorly understood. Data from experimental studies presented in this dissertation define a regulatory pathway in which the microRNA, MIR203 mediates the forfeiture of self-renewing capacity in mammary stem cells during differentiation through the repression of DeltaNP63alpha expression. Moreover, mature miR-203 expression was inversely correlated with an aggressive, pro-invasive phenotype in a panel of breast cancer cell lines, suggesting a role for DeltaNP63alpha in breast cancer progression. As a result, we sought to identify targets of DeltaNP63alpha that may mediate such tumorigenic activities. Here, we present data identifying the pro-metastatic chemokine receptor 4 gene (CXCR4) as a direct transcriptional target of DeltaNP63alpha, which subsequently mediates DeltaNP63alpha's cancer stem cell activities and chemotactic phenotype in breast cancer cells. This work suggests that DeltaNP63alpha may identify and regulate tumor-initiating cancer stem cells of high metastatic potential, which may be clinically relevant to target therapeutically to reduce breast cancer progression and metastasis.