This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adapter protein, which is implicated in innate immune regulation and apoptosis. A strong link to cancer has been recently recognized, when 68% of breast cancers inactivate the ASC gene. ASC modulates activity of transcription factors that are closely linked to mammary tumorigenesis by inducing genes that support proliferation, invasiveness and survival of tumor cells. However, the direct role of ASC in breast cancer is still elusive and needs to be determined. Our hypothesis is that ASC functions as a tumor suppressor gene in mammary epithelial cells by blocking aberrant NF-kappaB activity at the IKK complex. Silencing of ASC provides one mechanism for tumor cells to escape the well-balanced control of proliferation and apoptosis, resulting in the development of cancer. The objective of this study is to elucidate the function of ASC in breast cancer and to determine the mechanism by which loss of ASC expression promotes breast cancer. To achieve this purpose, we propose the following specific aims: 1.) To determine the molecular mechanism by which ASC silencing promotes breast cancer: 1A.) To determine the effect of ASC silencing on proliferation of breast cancer cells; 1B.) To evaluate apoptosis of breast cancer cells in which ASC has been blunted;1C.) To determine the mechanism by which ASC may regulate invasiveness of breast cancer cells; 2.) To evaluate the role of ASC in in vivo breast cancer initiation and progression. Our study is designed (1) to restore ASC expression by stable transfection of ectopic ASC into ASC deficient breast cancer cell lines, and (2) to knock-down expression of ASC by RNA interference in ASC proficient breast cancer cell lines to simulate ASC silencing. Characterization of genes associated with breast cancer susceptibility is necessary, if more efficient treatment options are to be developed.This study supports our long-term goal of understanding the molecular mechanisms of mammary tumorigenesis and to identify and characterize candidates for breast cancer prevention and therapy. ASC silencing occurs in most carcinomas. Therefore, we anticipate that results from this study are not only relevant for better understanding the progression of mammary carcinomas, but will be significant for several other types of carcinomas, as well.
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