CATECHOL-O-METHYLTRANSFERASE AND BREAST CANCER

描述：儿茶酚O-甲基转移酶（COMT）在 雌激素儿茶酚代谢物的雌激素失活， 包括乳房组织的外周组织。 COMT是由一个 一种在人群中具有多态性的基因，其中25%的高加索人 对于酶的低活性形式是纯合的。 鉴于 儿茶酚雌激素有助于乳腺癌的证据越来越多 COMT可能具有保护作用，因此推测 低活性COMT纯合子的女性 增加患乳腺癌的风险。 使用基于PCR的RFLP分析， 申请人的实验室，筛选了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 来自西马里兰州。 结果表明，低活性COMT基因型 绝经后妇女患乳腺癌的风险显著增加 女性（比值比=2.3; p=0.05）。 这种假设驱动的分子 一项流行病学研究首次表明，酶的多态性 参与活性雌激素代谢物失活的 患乳腺癌的风险增加。 本申请中描述的项目的目标是进行一项 严格的实验研究假设，减少COMT 活动导致氧化损伤增加，这种应激 时间有助于增加细胞转化和乳腺癌。 的 本项目的具体目标是：1）确定COMT的效果 对选定人乳腺中氧化损伤和应激的抑制 表达野生型（MCF-10 F）和变体（MCF-7）的上皮细胞系 2）确定野生型和变体的动力学 这些细胞系的胞质溶胶中COMT的2-OH甲基化形式 和雌二醇的4-OH儿茶酚;和3）确定COMT的作用 使用COMT-核酶转基因小鼠体内抑制乳腺癌。

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.