GENISTEIN AND CANCER PREVENTION--MECHANISMS AND MODELS

该提案是构成交互式ROI的三个项目之一 题为《大豆异黄酮的抗癌机制》的申请 染料木素“，其主要目标是确定 三羟基异黄酮染料木素的作用机制(S) 对几种癌症的化学预防作用。金雀异黄素和 二羟基异黄酮类大豆苷元在大豆中大量存在(2-3 mg/g) 大豆，但不存在于美国人饮食中的其他食物中。吃东西的女人 富含豆类食物的饮食患乳腺癌的几率比吃豆制品低得多 那些吃典型美式饮食的人。尽管染料木素长期以来一直是 众所周知，它具有微弱的雌激素活性，也已在体外试验中被证明 是许多蛋白酪氨酸激酶的抑制剂，并抑制 许多癌细胞株的生长，表明它可能具有重要的 在预防癌症方面的作用。然而，关键的细胞靶点是 金雀异黄素作为抗增生剂的作用尚未得到研究 已确认身份。这项建议的具体目的是确定：(1) 金雀异黄素对血清雌二醇和表皮生长因子的抑制作用 人乳腺癌细胞株在有无刺激下的生长 雌激素受体的表达；(2)金雀异黄素在人乳腺癌中的表达 生长因子刺激的细胞株抑制磷酸化 (A)雌激素受体；(B)EGF受体；(C) EGF激活的信号转导序列；(3)染料木素是否 抑制即刻早期表达的有丝分裂诱导 C-fos、c-jun和c-myc基因；(4)在乳腺癌大鼠模型中， 当膳食染料木素限制在25岁以下时，其影响更大。 在服用化学致癌物之前和期间的日龄 在50日龄(抗启动效应)时，或在第一个乳房之后 肿瘤已开始出现(进展促进作用)；(5)是否 金雀异黄素对雌性大鼠青春期细胞的影响 乳腺的分化和增殖；以及(6)是否 从青春期到给药时间的饮食中包含染料木素 降低了DMBA-DNA加合物的形成速度和数量 乳房。它的目的是这个项目应该建立一个理由 将大豆作为推荐食品使用的基础，以降低罹患癌症的风险 美国人的癌症。

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.