Green Tea and Reduction of Breast Cancer Risk

描述(由申请人提供)：这项提案的最终目标是全面了解茶儿茶素抑制人类乳腺癌发生的机制。绿茶儿茶素已被证明可以抑制啮齿动物的乳腺癌发生，流行病学研究表明，经常喝绿茶的女性降低了患乳腺癌的风险。然而，流行病学数据并不一致，这可能是由于儿茶素代谢的遗传差异。事实上，我们已经证明，只有在具有低活性儿茶酚-O-甲基转移酶(COMT)基因的女性中，饮用绿茶才与乳腺癌风险降低相关。这与COMT活性显著影响儿茶素代谢和排泄的理解是一致的。这项建议的目的是进行一项临床试验，以检验(来自实验动物和流行病学研究的)假设，即饮用绿茶可以降低乳腺癌风险，而且这种影响主要见于低活性COMT基因的女性。我们将通过评估绿茶儿茶素对根据COMT基因招募的女性乳腺癌生物标记物的影响来做到这一点。我们将在800名绝经后女性中进行一项随机、双盲、安慰剂对照试验，她们的乳房X光检查密度处于公认的乳腺癌危险因素的上半部分。800名高危女性(400名低活动型和400名高活动型COMT)将在12个月内每天服用800毫克表没食子儿茶素没食子酸酯(EGCG，最有效的茶儿茶素)或安慰剂药片。绿茶儿茶素将以多酚E(PPE)的形式给予，这是茶儿茶素的标准化制剂。我们的主要目标是确定补充12个月的PPE对下列公认的乳腺癌风险生物标志物的影响：乳房摄影密度；血浆胰岛素样生长因子1(IGF-1)、IGF结合蛋白3、雌酮、雌二醇、雄烯二酮和性激素结合球蛋白。我们的次要目标是确定PPE对下列乳腺癌风险生物标志物的影响：尿雌激素代谢物和血浆F2-异前列腺素。我们假设，PPE对这些生物标记物的有益影响将主要见于低活性COMT组。这是第一个评估绿茶儿茶素预防乳腺癌效果的随机、双盲、安慰剂对照试验。通过使用营养基因组学方法，这项有针对性的营养干预研究将有助于澄清绿茶降低乳腺癌风险的机制，并确定对绿茶最敏感的亚群。针对高危妇女制定可行的化学预防战略可能会对乳腺癌发病率和死亡率产生重大影响。公共卫生相关性：乳腺癌是西方国家的主要死亡原因，在亚洲的发病率正在上升。这项有针对性的营养干预研究将有助于阐明绿茶降低乳腺癌风险的机制，并确定对绿茶最敏感的亚群。针对高危妇女制定可行、无毒的化学预防战略可能会对乳腺癌发病率和死亡率产生重大影响。

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to gain a full understanding of the mechanisms by which tea catechins inhibit breast carcinogenesis in humans. Green tea catechins have been shown to inhibit mammary carcinogenesis in rodents, and epidemiological studies have shown that women who regularly drink green tea have reduced breast cancer risk. The epidemiological data are inconsistent, however, likely due to genetic differences in catechin metabolism. In fact, we have shown that green tea consumption is associated with reduced breast cancer risk only in women with the low-activity catechol-O-methyltransferase (COMT) genotype. This is consistent with the understanding that COMT activity significantly influences catechin metabolism and excretion. The purpose of this proposal is to perform a clinical trial to test the hypotheses (generated from experimental animal and epidemiological studies) that green tea consumption reduces breast cancer risk, and that this effect is seen primarily in women with the low-activity COMT genotype. We will do this by evaluating the effects of green tea catechins on breast cancer biomarkers in women who have been recruited on the basis of their COMT genotype. We will conduct a randomized, double-blind, placebo-controlled trial in 800 postmenopausal women who are in the upper half of mammographic density, a recognized risk factor for breast cancer. The 800 high-risk women (400 low-activity and 400 high-activity COMT genotype) will receive either 800 mg epigallocatechin gallate (EGCG, the most potent of the tea catechins) or placebo pills daily for 12 months. The green tea catechins will be given in the form of Polyphenon E (PPE), a standardized preparation of tea catechins. Our primary aims are to determine the effects of 12 months of PPE supplementation on the following recognized biomarkers of breast cancer risk: mammographic density; plasma insulin-like growth factor 1 (IGF-1), IGF binding protein 3, estrone, estradiol, androstenedione and sex hormone binding globulin. Our secondary aims are to determine the effects of PPE on the following proposed biomarkers of breast cancer risk: urinary estrogen metabolites and plasma F2-isoprostanes. We hypothesize that the beneficial effects of PPE on these biomarkers will be seen primarily in the low-activity COMT group. This is the first randomized, double- blind, placebo-controlled trial to assess the efficacy of green tea catechins on breast cancer prevention. By using a nutrigenomic approach, this targeted nutrition intervention study will help clarify the mechanisms by which green tea lowers breast cancer risk as well as identify a sub-population most responsive to green tea. The development of a viable chemoprevention strategy targeting high risk women could have a significant impact on breast cancer morbidity and mortality. PUBLIC HEALTH RELEVANCE: Breast cancer is a leading cause of death in Western countries and incidence is increasing in Asia. This targeted nutrition intervention study will help clarify the mechanisms by which green tea lowers breast cancer risk as well as identify a sub-population most responsive to green tea. The development of a viable non-toxic chemoprevention strategy targeting high risk women could have a significant impact on breast cancer morbidity and mortality.