Control of the Notch Signaling Pathway in Mammary Gland Development and Carcinogenesis by the Stem Cell Specific Transcription Factor DeltaNp63

The TP63 gene produces a series of transcription factors as a result of multiple promoter usage and alternative splicing. These protein products are members of the p53 family of transcription factors due to strong structural similarity with thousands of transcriptional targets. This thesis focuses on DeltaNp63&agr;, an N-terminally truncated protein product with the longest of three possible C-terminal regions. DeltaNp63&agr; is predominantly expressed in basal epithelia where it plays critical roles in stem cell self-renewal. Expression of this transcription factor influences a variety of signaling pathways to modulate development and maintain tissue stasis. The goal of this research was to investigate the relationship between DeltaNp63&agr; and the Notch signaling pathway in multiple mammary epithelial systems. DeltaNp63&agr; is expressed in the basal epithelia of the mammary gland including mammary stem cells, while Notch signaling modulates mammary epithelial lineage commitment, proliferation, and differentiation. Data throughout this thesis suggest that DeltaNp63&agr; promotes Notch signaling in the mammary gland and in breast cancer cells through a variety of targets within the Notch signaling cascade. This investigation lead to the elucidation of a mechanism for the regulation of mammary epithelial cell quiescence as a result of DeltaNp63&agr; promoting expression and activation of the Notch receptor, Notch3. Mammary stem cells require the ability to undergo cellular quiescence to maintain longevity and tissue stasis. However, breast cancer stem cells may also use this ability to exit the cell cycle for prolonged periods as a mechanism to resist the damaging effects of many chemotherapeutics. Evidence from this thesis suggests that targeting Notch3 in DeltaNp63&agr;-positive breast tumors may eliminate the ability of these cells to undergo quiescence, thus providing a therapeutic opportunity to eliminate cancer stem cells and possibly reduce the likelihood of tumor recurrence.