APC mutation and breast cancer: Prevention by curcumin

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DESCRIPTION (provided by applicant): Cancer of the breast represents a major cause of death in American women. Recent cancer statistics from the American Cancer Society have estimated 32% incidence (269,000 new breast cancer cases) and a 21% mortality (40,410 breast cancer related deaths) to breast cancer in the US in 2005. Only 5-10% of all breast cancers have a hereditary basis, most sporadic breast cancers occur spontaneously in women with no overt family history, thereby presenting a serious challenge to identify the genes which regulate the progression breast cancers. A significant challenge, is to identify early-occurring genetic/ molecular changes relevant to the development of sporadic breast cancer. Recent epidemilogical evidence suggest that defects in ARC gene leads to altered signaling thereby enhancing the multistep carcinogenic process in the breast. Approximately 2 in 5 human breast cancers are reported to carry mutation or loss of function in ARC gene. 'Min' mice with mutations in ARC gene are predisposed to spontaneous mammary tumors and show susceptibility to carcinogenic progression by chemical carcinogens. We have developed a novel cell culture model from these mutant mice and have shown their aberrant proliferation property towards transformation. We have shown that the altered molecular markers for tumorigenicity can be prevented by dietary agent, Curcumin, the yellow curry powder extensively used in Asian countries. We propose to extend our study to identify the molecular changes due to carcinogen END, in Min mouse mammary gland and its preventiion by curcumin. We will use genomic and proteomic approach to identify the target molecular markers and pathways of carcinogenic transformation. Thus, use of our newly developed, relevant breast cell-culture model from APC gene knockout mouse, provides an innovative mechanistic in vitro and in vivo Min mouse model for investigating, 1) how mutation in Apc gene promotes tumor formation and 2) evaluating the mechanistic efficacy of potential chemopreventive agent curcumin.Outcome of this study will help us identify role of new gene APC,in breast cancer progression and also support the clinical relevance. Thus, the present research direction represents a novel approach to study the molecular and biological manifestations on gene-environment and gene-nutrition interactions impacting on breast carcinogenesis and prevention.