APC mutation and breast cancer: Prevention by curcumin

描述(申请人提供)：乳腺癌是美国女性的主要死因。美国癌症协会最近的癌症统计数据估计，2005年美国乳腺癌的发病率为32%(新增269,000例乳腺癌病例)，死亡率为21%(与乳腺癌相关的死亡40,410例)。在所有乳腺癌中，只有5%-10%有遗传基础，大多数散发性乳腺癌发生在没有明显家族史的妇女身上，因此对识别调控乳腺癌进展的基因提出了严峻的挑战。一个重大的挑战是确定与散发性乳腺癌的发展相关的早期发生的基因/分子变化。最近的流行病学证据表明，ARC基因的缺陷导致信号改变，从而增强了乳腺癌的多步骤致癌过程。据报道，大约五分之二的人类乳腺癌携带ARC基因突变或功能丧失。带有ARC基因突变的“MIN”小鼠容易患自发性乳腺癌，并对化学致癌物的致癌进展表现出易感性。我们从这些突变的小鼠身上开发了一种新的细胞培养模型，并显示了它们在转化过程中的异常增殖特性。我们已经证明，改变的致瘤性分子标记可以通过饮食制剂姜黄素来预防，姜黄素是一种在亚洲国家广泛使用的黄色咖喱粉。我们建议扩大我们的研究范围，以确定致癌物END在Min小鼠乳腺中的分子变化以及姜黄素的预防作用。我们将使用基因组和蛋白质组的方法来确定致癌转化的靶分子标志物和途径。因此，利用我们新开发的APC基因敲除小鼠乳腺细胞培养模型，为研究APC基因突变如何促进肿瘤的形成和评价潜在的化学预防药物姜黄素的机制疗效提供了一个创新的体外和体内Min小鼠模型。因此，本研究方向为研究基因-环境和基因-营养相互作用在乳腺癌发生和预防中的分子生物学表现提供了新的途径。

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.