| Efforts to elucidate the events that account for breast cancer initiation have focused sharply on a small subset of mammary epithelial cells, referred to in this document at mammary stem cells, whose features may enable them to accumulate and harbor mutations, and produce a broad spectrum of breast cancer subtypes with a high degree of cellular heterogeneity that is common to human breast tumors. Progress towards understanding the underlying causes of breast cancer recurrence have focused increasing attention on a small population of cells within a breast tumor, referred to in this document as breast cancer stem cells, with two specific features; therapeutic resistance and tumorigenicity. Several striking similarities between these two populations exist that suggest that the mechanisms by which mammary stem cells preserve their replicative capacity, developmental potency and prolonged life span overlap with the mechanisms that account for therapeutic resistance and tumorigenicity in breast cancer-initiating cells. Studies presented in this dissertation focus upon the expression and activity of TP63 a gene whose products are structurally related to the tumor suppressor, p53. TP63 is required for the preservation of adult stem cells within diverse epithelial structures including the mammary gland, however the mechanisms by which this preservation is achieved have not been fully elucidated. Experimental data derived from studies presented in this dissertation support a model in which the predominant isoform of TP63, DeltaNp63alpha preserves the features of mammary stem cells by enforcing a state of proliferative quiescence that enables mammary stem cells to retain their proliferative capacity and developmental potency over a prolonged life span. Similarly this function of DeltaNp63alpha may also confer therapeutic resistance to breast cancer stem cells, which would have important implications for alternative therapeutic strategies to reduce breast cancer recurrence. |
