Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis
Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis
复制标题
DOI：
10.1093/carcin/bgh065
复制
发表时间：
2004-05-01
期刊：
影响因子：
4.7
通讯作者：
Hilakivi-Clarke, L
中科院分区：
文献类型：
--
作者：
Cabanes, A;Wang, M;Hilakivi-Clarke, L
在动物模型和人类中，青春期前接触大豆或其生物活性成分染料木黄酮可降低后来患乳腺癌的风险。我们调查了这是否可能是由于报道的染料木素的雌激素特性。我们的研究表明，在出生后第7天至20至10天期间，青春期前每天暴露于17 - β -雌二醇（E2）可降低以后发生7,12-二甲基苯[a]蒽（DMBA）诱导的乳腺肿瘤的风险。乳腺形态学评估显示，青春期前暴露于E2和染料木素（每天50杯）可减少乳腺上皮面积和终末芽（teb）的数量，增加小叶-肺泡结构的密度，表明这些暴露诱导了分化恶性转化目标的消除。下一步，研究E2和染料木素的保护作用机制。E2被证明上调BRCA1， BRCA1是一种参与DNA损伤修复过程和细胞分化的肿瘤抑制基因，并下调雌激素受体(ER)- α的活性。在3、8和16周龄时，暴露于E2或染料木素的大鼠的乳腺中BRCA1 mRNA的表达上调。青春期前暴露于E2会降低乳腺中的er - α水平，而青春期前暴露于染料木黄酮则会产生相反的效果。我们的研究结果表明，青春期前雌激素暴露可能通过诱导乳腺中BRCA1的持续上调来降低后期乳腺癌的风险。
Prepubertal exposure to soy or its biologically active component genistein reduces later breast cancer risk in both animal models and human populations. We investigated whether that might be due to reported estrogenic properties of genistein. Our study indicated that daily prepubertal exposures between postnatal days 7 and 20 to 10 mug 17beta-estradiol (E2) reduced later risk of developing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Assessment of mammary gland morphology revealed that both prepubertal E2 and genistein (50 mug daily) exposures reduced the size of mammary epithelial area and number of terminal end buds (TEBs) and increased the density of lobulo-alveolar structures, suggesting that these exposures induced elimination of targets for malignant transformation by differentiation. Next, the mechanisms mediating the protective effects of E2 and genistein were investigated. E2 is shown to up-regulate BRCA1, a tumor suppressor gene that participates in DNA damage repair processes and cell differentiation and that down-regulates the activity of estrogen receptor (ER)-alpha. The expression of BRCA1 mRNA was up-regulated in the mammary glands of rats exposed to E2 or genistein during prepuberty, when determined at the ages of 3, 8 and 16 weeks. Prepubertal E2 exposure reduced ER-alpha levels in the mammary gland, while prepubertal genistein exposure had an opposite effect. Our results suggest that prepubertal estrogenic exposures may reduce later breast cancer risk by inducing a persistent up-regulation of BRCA1 in the mammary gland.