CATECHOL-O-METHYLTRANSFERASE AND BREAST CANCER

描述：儿茶酚O-甲基转移酶(COMT)在 大鼠雌激素儿茶酚代谢产物的雌激素失活 外周组织，包括乳房组织。COMT由单个 在有25%高加索人的人群中存在多态基因 对于低活性形式的酶来说是纯合的。给定 越来越多的证据表明邻苯二酚雌激素对乳房有贡献 癌症发生和COMT可能起到保护作用，这是假设的 低活性COMT纯合子的女性将处于 增加患乳腺癌的风险。使用一种基于PCR的RFLP分析 从申请人的实验室中筛选出116例病例和116例匹配的对照 一项嵌套在大型(30,000)队列研究中的前瞻性病例对照研究 来自马里兰州西部。结果表明，低活性COMT基因 使绝经后患乳腺癌的风险显著增加 女性(优势比=2.3；P=0.05)。这种假说驱动的分子 流行病学研究首次表明一种酶的多态 与活性雌激素代谢物的失活有关 增加了患乳腺癌的风险。 本申请中描述的项目的目标是进行 对降低COMT假说的严格实验研究 活动会导致氧化损伤增加，这种压力会导致 时间有助于增加细胞转化和乳腺癌。这个 本项目的具体目标是：1)确定COMT的效果 对人乳房氧化损伤和应激的抑制作用 表达野生型(MCF-10F)和变异型(MCF-7)的上皮细胞系 COMT的形式；2)测定野生型和变异型的动力学 这些细胞系胞浆中2-羟基甲基化的COMT形式 和4-羟基雌二醇儿茶酚；3)测定COMT的作用 COMT-ribozyme转基因小鼠体内对乳腺癌的抑制作用。

DESCRIPTION: Catechol O-methyltransferase (COMT) has a major role in the inactivation of the estrogen of the estrogen catechol metabolites in peripheral tissues including breast tissue. COMT is coded for by a single gene that is polymorphic in the human population with 25% of Caucasians being homozygous for a low activity form of the enzyme. Given the accumulating evidence that catechol estrogens contribute to breast carcinogenesis and that COMT may play a protective role, it is hypothesized that women homozygous for the low activity form of COMT would be at increased risk for breast cancer. Using a PCR-based RFLP assay developed in the applicant's lab, 116 cases plus 116 matched controls were screened from a prospective case-control study nested within a large (30,000) cohort study from Western Maryland. The results show that the low activity COMT genotype confers a significantly increased risk for breast cancer in postmenopausal women (odds ratio=2.3; p=0.05). This hypothesis-driven molecular epidemiology study is the first to suggest that a polymorphism in an enzyme involved in the inactivation of a reactive estrogen metabolite is associated with an increased risk for breast cancer. The goal of the project described in this application is to conduct a rigorous experimental investigation of the hypothesis that decreased COMT activity results in increased oxidative damage and this stress that with time contributes to increased cell transformation and breast cancer. The specific aims of this project are: 1) to determine the effects of COMT inhibition on oxidative damage and stress in selected human breast epithelial cell lines expressing the wild-type (MCF-10F) and variant (MCF-7) forms of COMT; 2) to determine the kinetics of the wild type and variant forms of COMT in cytosols from these cell lines for methylation of the 2-OH and 4-OH catechols of estradiol; and 3) to determine the effects of COMT inhibition on breast cancer in vivo using a COMT-ribozyme transgenic mouse.