Analysis of Apaf-1 and Caspase 9 in Tumorigenesis
- Abstract:
- My long-term goal is to identify new components of tumor suppressor networks that are important in breast cancer. My initial proposal focused on apoptosis, and how components of the apoptotic machinery' influence breast carcinogenesis and chemotherapeutic responses. For several reasons, these studies were abandoned to focus on cellular senescence. Senescence is a permanent cell cycle arrest program that is conceptually similar to apoptosis and is controlled by the p53, p16, and Rb tumor suppressors (which are important in breast carcinogenesis). I am currently identifying components of the senescence machinery' and determining how they suppress proliferation. I have shown that senescence is accompanied by changes in chromatin structure that depend on the p16/Rb tumor suppressor pathway and lead to the repression of growth regulatory genes. I have also generated chimeric mice harboring ES cells with a targeted disruption of one putative component of the silencing program. Future studies will examine the impact of these mechanisms on transformation in vitro and tumorigenesis in vivo, as well as their ability to modulate the cytotoxicity of anticancer drugs. These studies are guided by our understanding of apoptosis, and promise to provide new insights into a new program of tumor suppression in breast cancer.