Modulation of p53-mediated apoptosis in the murine mammary gland

The tumor-suppressor gene, TP53, plays a major role in surveillance of cellular and genomic integrity, functioning in cell cycle regulation, repair of damaged DNA, and deletion of malfunctioning or defective cells. The latter is achieved through apoptosis, a mechanism of programmed cell death, which is important in both normal morphogenesis and suppression of tumorigenesis. The loss of p53 function in breast cancer has been the subject of intensive study, however, not much is known about how p53 functions in the normal mammary gland to mediate its protective apoptotic responses. The aim of this dissertation was to examine p53-mediated cell death in the murine mammary epithelial cells in response to two distinct apoptotic stimuli: exposure to ionizing radiation and detachment from an appropriate substratum. The first component of this work examined the role p53 plays in mediating apoptosis in response to gamma-radiation during distinct stages of post-natal mammary gland. The second part of this dissertation focused on whether detachment of epithelial cells from their extracellular matrix results in cell death that is p53-dependent or -independent. Results from these experiments demonstrate a requirement for functionally active p53 in radiation-induced cell death, and show that the proliferative capacity of the mammary gland at time of radiation exposure predicts the robustness of this apoptotic response. In contrast, detachment from substratum can trigger both p53-dependent and -independent cell death in mammary epithelial cells. However, apoptosis induced by the specific abrogation of β1 integrin-ligand interaction appears to proceed through a p53-dependent mechanism