APC mutation and breast cancer: Prevention by curcumin

APC 突变与乳腺癌：姜黄素预防

• 批准号: 7132974
• 负责人: Meena Katdare
• 金额: $ 29.82万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7132974
• 关键词: apoptosis; breast neoplasms; cancer prevention; carcinogenesis; gene mutation; genes; mammary gland; model

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.

描述（由申请人提供）：乳腺癌是美国妇女死亡的主要原因。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%（269，000例新发乳腺癌病例），死亡率为21%（40，410例乳腺癌相关死亡）。所有乳腺癌中只有5-10%具有遗传基础，大多数散发性乳腺癌自发发生在没有明显家族史的女性中，从而对确定调节乳腺癌进展的基因提出了严峻的挑战。一个重要的挑战是确定与散发性乳腺癌发展相关的早期发生的遗传/分子变化。最近的药理学证据表明，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。ARC基因突变的“Min”小鼠易患自发性乳腺肿瘤，并对化学致癌物的致癌进展表现出易感性。我们已经从这些突变小鼠中开发了一种新的细胞培养模型，并显示了它们对转化的异常增殖特性。我们已经证明，改变的致瘤性分子标记可以通过饮食剂姜黄素来预防，姜黄素是亚洲国家广泛使用的黄色咖喱粉。我们建议扩展我们的研究，以确定致癌物END在Min小鼠乳腺中引起的分子变化以及姜黄素的预防作用。我们将利用基因组学和蛋白质组学的方法来确定致癌转化的靶分子标记和途径。因此，使用我们新开发的来自APC基因敲除小鼠的相关乳腺细胞培养模型，为研究1）Apc基因突变如何促进肿瘤形成和2）评估潜在化学预防剂姜黄素的机制功效提供了创新的体外和体内机制Min小鼠模型。在乳腺癌进展中的作用，也支持临床相关性。因此，目前的研究方向代表了一种新的方法来研究基因-环境和基因-营养相互作用对乳腺癌发生和预防的分子和生物学表现。