IN VITRO INDUCTION & MODULATION OF MAMMARY PRENEOPLASIA

体外诱导

• 批准号: 3458101
• 负责人: NITIN T TELANG
• 金额: $ 8.13万
• 依托单位: MEMORIAL HOSPITAL FOR CANCER & ALLIED DI
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-08 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3458101
• 关键词: 6 thioguanine; DNA; DNA repair; antineoplastics; athymic mouse; benzanthracenes; breast neoplasms; calcium; cancer prevention; cellular oncology; chemical carcinogen; chemical carcinogenesis; disease /disorder model; drug resistance; gene expression; histopathology; human tissue; hyperplasia; laboratory mouse; molecular oncology; mutant; neoplasm /cancer genetics; neoplasm /cancer nutrition therapy; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic cell; neoplastic growth; nitrosourea; omega 3 fatty acid; ouabain; preneoplastic state; saturated fatty acids; tissue /cell culture; vitamin therapy

This research proposal is interested in the mechanisms involved in human mammary carcinogenesis and its prevention. In murine systems the process of mammary cell transformation progresses via distinct steps of initiation, promotion and progression. The critical molecular and cellular events characterizing human mammary cell transformation have not been identified. Dietary interventions involving restriction of polyunsaturated omega-6 fatty acids, supplementation with saturated fatty acids and polyunsaturated omega-3 fatty acids or hyperalimentation with retinoids inhibit, retard or prevent murine mammary tumorigenesis. The efficacy of such dietary interventions to prevent human mammary cancer is yet to be validated. With comparative studies on the newly developed human mammary explant culture system and on the well-standardized murine mammary explant culture system the present proposal seeks to test the hypothesis that the process of mammary cell transformation progresses via similar molecular and cellular events in the two systems, and that the prototype modulators of murine mammary tumorigenesis can inhibit, retard or prevent the preneoplastic steps in human mammary cell transformation. The explant cultures will be exposed to the carcinogens, 7,12- dimethylbenz(a) anthracene (DMBA) and N-nitroso-N-methylurea (NMU). The in vitro response of the tissue to the carcinogens will be evaluated at the molecular level by measuring the induction of DNA damage/repair and 6-thioguanine and/or Ouabain resistant (TGr/OUr) mutants. The cellular response to the carcinogens will be assessed by determining the incidence of ductal or alveolar hyperplasia with atypia and by the morphogenetic and tumorigenic potential of the transplanted atypical lesions. In the cell cultures derived from the 'preneoplastic' lesions, the persistance of 'transformed' phenotype will be demonstrated by measuring the cell growth in calcium and/or serum depleted medium, persistance of TGr/OUr mutants, acquisition of anchorage-independent growth and formation of atypical epithelial hyperplasia and/or tumor at the transplant site. The modulatory influence of selected fatty acids and retinoids will be evaluated by measuring the alterations induced in the quantitative parameters detailed above. The proposal will provide a basis for future studies with focus in more detail on the mechanisms in human mammary carcinogenesis and its prevention.

本研究计划对涉及的机制感兴趣 人类乳腺癌的发生及其预防。 在小鼠中 系统乳腺细胞转化过程的进展 通过启动、促进和进展的不同步骤。 这 人类特征的关键分子和细胞事件 乳腺细胞转化尚未确定。 饮食 涉及限制多不饱和 omega-6 的干预措施 脂肪酸，补充饱和脂肪酸和 多不饱和 omega-3 脂肪酸或营养过剩 类维生素A抑制、延迟或预防小鼠乳腺 肿瘤发生。 此类饮食干预措施的功效 预防人类乳腺癌尚待验证。 和 新发育的人类乳房的比较研究 外植体培养系统和标准化的小鼠 乳腺外植体培养系统 本提案旨在 检验乳腺细胞过程的假设 转化通过相似的分子和细胞进行 两个系统中的事件，以及原型调制器 小鼠乳腺肿瘤的发生可以抑制、延缓或预防 人类乳腺细胞转化的肿瘤前步骤。 这 外植体培养物将暴露于致癌物质，7,12- 二甲基苯并(a)蒽 (DMBA) 和 N-亚硝基-N-甲基脲 （NMU）。 组织对致癌物的体外反应将 通过测量诱导在分子水平上进行评估 DNA 损伤/修复和 6-硫鸟嘌呤和/或哇巴因抗性 (TGr/OUr) 突变体。 细胞对致癌物的反应 通过确定导管或肺泡的发生率来评估 具有异型性的增生以及形态发生和致瘤性 移植非典型病变的潜力。 在细胞培养物中 源自“肿瘤前”病变， “转化”的表型将通过测量 细胞在钙和/或血清耗尽的培养基中生长，持久性 TGr/OUr 突变体，获得锚定独立 非典型上皮增生的生长和形成和/或 移植部位的肿瘤。 的调节影响 选定的脂肪酸和类维生素A将通过测量进行评估 详细定量参数引起的变化 多于。 该提案将为未来的研究奠定基础 更详细地关注人类乳腺的机制 致癌作用及其预防。