GENISTEIN AND CANCER PREVENTION--MECHANISMS AND MODELS

金雀花素与癌症预防——机制和模型

• 批准号: 2102415
• 负责人: STEPHEN BARNES
• 金额: $ 13.74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2102415
• 关键词: DNA damage; adduct; benzanthracenes; breast neoplasms; cancer prevention; cell cycle; chemical carcinogenesis; chemoprevention; clone cells; disease /disorder model; epidermal growth factor; estradiol; estrogen receptors; flavonoids; gene expression; laboratory rat; neoplastic cell; nutrition aspect of cancer; nutrition related tag; oncogenes; phosphorylation; soybeans; tumor promoters

This proposal is one of three projects forming an Interactive ROI application entitled "Anti-cancer mechanisms of the soy isoflavone genistein", the principle objective of which is to determine the mechanism(s) by which the trihydroxyisoflavone genistein exerts its chemopreventive effect against several types of cancer. Genistein and the dihydroxyisoflavone daidzein are present in large quantities (2-3 mg/g) in soy, but are not found in other foods in the American diet. Women who eat a diet rich in soy foods have a much lower incidence of breast cancer than those who eat a typical American diet. Although genistein has long been known for its weak estrogenic properties, it has also been shown in vitro to be an inhibitor of many protein tyrosine kinases and to inhibit the growth of many cancer cell lines, suggesting that it may have an important role in the prevention of cancer. However, the crucial cellular targets of genistein in its role as an anti-proliferative agent have not yet been identified. The specific aims of this proposal are to determine: (1) the inhibitory effects of genistein on the serum-,estradiol- and EGF- stimulated growth of a human breast cancer cell line with and without expressed estrogen receptor; (2) whether genistein in human breast cancer cell lines stimulated by growth factors inhibits the phosphorylation of (a) the estrogen receptor, (b) the EGF receptor; (c) key kinases in the signal transduction sequence activated by EGF; (3) whether genistein suppresses the mitogenic induction of expression of the immediate early genes c-fos, c-jun and c-myc; (4) in a rat model of breast cancer, whether dietary genistein has a larger effect when limited to the period from 25 days of age up to and during the administration of the chemical carcinogen at 50 days of age (anti-initiation effect), or after the first mammary tumors have begun to appear (progression-promotion effect); (5) whether genistein administered during puberty in female rats alters cell differentiation and proliferation in the mammary; and (6) whether inclusion of genistein in the diet from puberty to time of administration of DMBA decreases the rate of formation and amount DMBA-DNA adducts in the mammary. It is intended that this project should establish a rationale basis for the use of soy as a recommended foodstuff to lower the risk of cancer in Americans.

该提案是形成交互式投资回报率的三个项目之一 题为“大豆异黄酮的抗癌机制”的申请 金雀异黄素”，其主要目标是确定 三羟基异黄酮金雀异黄酮发挥作用的机制 对多种癌症有化学预防作用。金雀异黄酮和 二羟基异黄酮黄豆苷原大量存在于 (2-3 mg/g) 大豆，但在美国饮食中的其他食物中不存在。吃东西的女人 富含大豆食品的饮食与乳腺癌的发病率相比要低得多 那些吃典型的美国饮食的人。尽管金雀花素长期以来 以其弱雌激素特性而闻名，它也在体外得到了证明 是许多蛋白酪氨酸激酶的抑制剂并抑制 许多癌细胞系的生长，表明它可能具有重要的作用 对预防癌症的作用。然而，关键的细胞靶标 金雀异黄素作为抗增殖剂的作用尚未得到证实。 确定。本提案的具体目标是确定：(1) 金雀异黄酮对血清、雌二醇和 EGF- 的抑制作用 刺激人类乳腺癌细胞系的生长 表达雌激素受体； (2)金雀花素是否与人类乳腺癌有关 生长因子刺激的细胞系抑制磷酸化 (a)雌激素受体，(b)EGF受体； (c) 关键激酶 EGF激活的信号转导序列； (3)是否为金雀异黄酮 抑制立即早期表达的促有丝分裂诱导 基因c-fos、c-jun和c-myc； (4) 在乳腺癌大鼠模型中，是否 当限制在 25 岁以下期间时，饮食金雀异黄素具有更大的影响 服用化学致癌剂之前的年龄以及服用化学致癌剂期间的天数 50 日龄时（抗启动效应），或第一次哺乳后 肿瘤已经开始出现（促进进展作用）； (5) 是否 雌性大鼠青春期注射金雀异黄素可改变细胞 乳腺的分化和增殖； (6) 是否 从青春期到给药期间将金雀异黄酮纳入饮食中 DMBA 降低了 DMBA-DNA 加合物的形成速率和数量 乳房。该项目旨在建立一个理由 使用大豆作为推荐食品以降低患病风险的依据 美国人的癌症。