Genistein action in the prepubertal mammary gland in a chemoprevention model
Genistein action in the prepubertal mammary gland in a chemoprevention model
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DOI：
10.1093/carcin/23.9.1467
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发表时间：
2002-09-01
期刊：
影响因子：
4.7
通讯作者：
Lamartiniere, CA
中科院分区：
文献类型：
--
作者：
Cotroneo, MS;Wang, J;Lamartiniere, CA
大豆含量高的饮食与许多健康益处有关，包括降低乳腺癌的发病率。大豆植物雌激素，染料木素，被假设为有助于通过与雌激素受体（ER）α和/或β的相互作用乳腺化学预防。这些类固醇信号传导途径被认为通过与表皮生长因子（EGF）信号传导途径的复杂双向相互作用来控制乳腺的增殖和分化。目前的工作旨在研究这两个途径在青春期前乳腺生长中的作用。雌性Sprague-Dawley CD大鼠在第16、18和20天注射染料木黄酮（500 μ g/g体重）或苯甲酸雌二醇（EB）（500 ng/g体重）。对21日龄大鼠乳腺的整体贴装分析表明，与给予溶剂二甲亚砜（DMSO）的动物相比，两种处理均导致末端芽（TEB）显著增加，导管分支增加。通过用2 mg ICI 182，780/kg体重（一种类固醇抗雌激素）预处理阻断ER功能，可抑制这两种作用。乳腺提取物的免疫印迹分析表明，用EB或染料木黄酮处理后，表皮生长因子受体（EGFR）和孕酮受体（PR）表达增加。通过免疫沉淀/免疫印迹法测定的酪氨酸磷酸化EGFR也增加，但当标准化为总受体时，没有净效应。EGFR、促分裂原活化激酶激酶（MEK 1和2）和细胞外信号调节激酶1和2（ERK 1和2）的下游靶点的表达和磷酸化未受到显著影响。抗雌激素预处理阻止了EGFR、磷酸化EGFR和PR的增加。数据表明染料木黄酮在乳腺增殖和分化中的基于ER的作用机制，这可以导致对乳腺癌的保护。
A diet high in soy is associated with many health benefits, including reduced incidence of breast cancer. The soy phytoestrogen, genistein, is hypothesized to contribute to mammary chemoprevention via interaction with estrogen receptors (ERs) alpha and/or beta. These steroid signaling pathways are believed to exert control over proliferation and differentiation of the mammary gland by a complex bidirectional interaction with the epidermal growth factor (EGF) signaling pathway. The current work was designed to study the role of these two pathways in prepubertal mammary gland growth. Female Sprague-Dawley CD rats were injected with genistein (500 mug/g body wt) or estradiol benzoate (EB) (500 ng/g body wt) on days 16, 18 and 20. Whole mount analysis of mammary glands from 21-day-old rats showed that both treatments resulted in significantly increased terminal end buds (TEBs), and increased ductal branching, compared with animals given the vehicle, dimethylsulfoxide (DMSO). Both effects were inhibited by blockage of ER function by pre-treating with 2 mg ICI 182,780/kg body wt, a steroidal anti-estrogen. Immunoblotting analyis of mammary gland extracts demonstrated increased epidermal growth factor receptor (EGFR) and progesterone receptor (PR) expression following treatment with EB or genistein. Tyrosine-phosphorylated EGFR, as measured by immunoprecipitation/immunoblotting was also increased, but when normalized to total receptors, there was no net effect. The expression and phosphorylation of downstream targets of the EGFR, mitogen activating kinase kinase (MEK 1 and 2) and extracellular signal regulated kinases 1 and 2 (ERK 1 and 2) were not significantly affected. Anti-estrogen pre-treatment prevented the increase in EGFR, phospho-EGFR and PR. The data indicate an ER-based mechanism of action for genistein in mammary gland proliferation and differentiation, which can lead to protection against mammary cancer.