Breast Cancer Chemoprevention Potential of Common Spices

描述(申请人提供)：女性激素，1715-雌二醇(E_2)及其代谢物，特别是4-羟基-E_2(4E_2)，与乳腺癌有关。据认为，过量的雌激素暴露会导致细胞增殖和DNA氧化损伤，这可能导致基因突变，最终导致乳腺癌。越来越清楚的是，乳腺癌死亡率的问题不能仅靠治疗来解决。因此，人们的注意力理所当然地转向检测暴露和疾病预防的早期标志。与目前的趋势不同，这一应用集中在属于一个植物科的常见香料上，以研究它们对抗雌激素介导的乳腺癌的潜力。我们推测，菊科常见香料(八角、香菜、香菜、孜然、小茴香、小茴香和小茴香)中存在的植物化学物质将有利于改变雌激素代谢、DNA氧化损伤和细胞增殖，最终减少乳腺肿瘤的发生。所有六种香料提取物的结果都显示，通过抑制P450活性和/或清除羟基自由基，以及体内抗增殖活性，显著减少了雌激素介导的DNA氧化损伤，支持了我们的工作假说。我们的主要目标是根据其抑制雌激素介导的乳腺肿瘤发生的作用模式来识别有效的香料，并将早期标记物与肿瘤指数相关联。具体地说，i)确定香料在短期体内测试中有利于调节雌激素代谢、氧化DNA加合和细胞增殖的潜力；ii)确定测试香料抑制雌激素介导的乳腺肿瘤发生的有效性，并将早期标志物的调节与肿瘤指数相关；以及iii)确定两种选定香料的提取物对抗雌激素介导的乳腺癌的潜力。该项目的数据将确定具有抑制乳腺癌潜力的香料，并建立早期生物标记物与肿瘤指数的关联。未来将对有效提取物进行分级，并对活性亚组分和纯化成分(S)进行抗雌激素致癌效果测试，以及对早期生物标志物的影响。因此，早期的生物标记物可以在病理可检测到的病变发生之前很久就识别出可能处于患乳腺癌高危状态的女性，并通过使用普通家用香料进行干预来预防疾病。

DESCRIPTION (provided by applicant): The female hormone, 1715-estradiol (E2) and its metabolites, particularly, 4-hydroxy-E2 (4E2), have been implicated in breast cancer. It is proposed that excessive estrogen exposure causes cell proliferation, and oxidative DNA damage, which may lead to gene mutations and ultimately breast cancer. It has become increasingly clear that the problem of breast cancer mortality cannot be solved by treatment alone. Therefore, attention has rightfully turned to the detection of early markers of exposure and disease prevention. Unlike the current trend, this application focuses on common spices belonging to one plant family for their potential against estrogen-mediated breast cancer. We hypothesize that phytochemicals present in common spices belonging to the Apiaceae family (anise, caraway, coriander, cumin, dill, and fennel) will favorably alter estrogen metabolism, oxidative DNA damage and cell proliferation, and ultimately diminish the mammary tumorigenesis. Results obtained from extracts of all the six spices have shown drastic reduction of estrogen-mediated oxidative DNA damage by inhibiting P450 activity and/or scavenging hydroxy radicals, as well as antiproliferative activity in vivo, supporting our working hypothesis. Our major objectives are to identify efficacious spices based on their modes of action to inhibit estrogen-mediated mammary tumorigenesis, and to correlate early markers with tumor indices. Specifically, i) determine potential of the spices in short-term in vivo assays to favorably modulate estrogen metabolism, oxidative DNA adduction, and cell proliferation; ii) determine efficacy of test spices to inhibit estrogen-mediated mammary tumorigenesis, and correlate modulation of early markers with tumor indices; and iii) determine potential of extracts of two selected spices against estrogen-mediated mammary cancer. Data resulting from this project will identify spices with the potential to inhibit breast cancer, and establish an association of early biomarkers with tumor indices. Efficacious extracts will in future be fractionated and active subfractions and purified component(s) will be tested for their efficacy against estrogen carcinogenicity and their effects on early biomarkers. Thus, the early biomarkers may identify women who may be at the higher risk of developing breast cancer much before the onset of pathologically detectable lesions, and prevent the disease by intervention with common house-hold spices.