Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates β-catenin signaling in mammary epithelial cells
Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates β-catenin signaling in mammary epithelial cells
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DOI：
10.1093/carcin/bgn279
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发表时间：
2009-02-01
期刊：
影响因子：
4.7
通讯作者：
Simmen, Rosalia C. M.
中科院分区：
文献类型：
--
作者：
Su, Ying;Simmen, Rosalia C. M.
乳腺癌的风险是高度可改变的饮食；然而，潜在的机制，饮食保护，以防止乳腺癌的发生仍然知之甚少。一部分乳腺癌与β-连环蛋白的稳定性和c-Myc表达的放大有关。我们最近发现，饮食中暴露于大豆异黄酮染料木素(Gen)抑制了体内大鼠乳腺上皮细胞中Wnt的转导。在这里，我们探讨了Gen对细胞黏附蛋白E-钙粘附素表达的作用，以下调β-连环素的原癌基因功能。在饮食Gen暴露的雌性大鼠的乳腺中，E-钙粘附素和β-连环素蛋白水平增加，同时β-酪蛋白基因表达增加。在HC11小鼠乳腺上皮细胞中，Gen抑制基础细胞和Wnt-1诱导的细胞增殖，并减弱Wnt-1靶向c-Myc和Cyclin D1的表达。而Gen对E-cadherin转录本水平无影响，膜E-cadherin蛋白和E-cadherin-β-catenin黏附复合体的丰度增加，同时下调WNT-1诱导的胞浆中游离β-catenin的积聚。基因抑制Wnt诱导的c-Myc表达可被雌激素受体(ER)β特异性激动剂而非ERα特异性激动剂所模拟，并随着ER-β表达的丧失而减弱，这与E-钙粘素表达的减少一致。靶向E-钙粘素的小干扰RNA消除了Gen对Wnt刺激的c-Myc表达的抑制，并促进了Gen诱导基础c-Myc转录水平和随后的增殖。我们的研究将E-钙粘素确定为Gen细胞靶点，并证明乳腺上皮细胞对Gen反应的二分性可能与细胞E-钙粘素的表达有关。
Breast cancer risk is highly modifiable by diet; however, mechanisms underlying dietary protection against mammary tumorigenesis remain poorly understood. A proportion of breast carcinomas is associated with deregulation of beta-catenin stability and amplification of c-Myc expression. We recently showed that dietary exposure to the soy isoflavone genistein (Gen) inhibited Wnt transduction in rat mammary epithelial cells in vivo. Here, we explored the role of Gen on cell adhesion protein, E-cadherin, expression to downregulate beta-catenin proto-oncogene function. In mammary glands of female rats exposed to dietary Gen, E-cadherin and beta-catenin protein levels were increased, concurrent with higher beta-casein gene expression. In HC11 mouse mammary epithelial cells, Gen diminished basal and Wnt-1-induced cell proliferation and attenuated Wnt-1 targets c-Myc and Cyclin D1 expression. Whereas, Gen had no effect on E-cadherin transcript levels, the abundance of membrane E-cadherin protein and of E-cadherin-beta-catenin adhesion complex was increased by Gen, attendant with downregulation of Wnt-1-induced free beta-catenin accumulation in cytosol. Gen inhibition of Wnt-induced c-Myc expression was mimicked by an estrogen receptor (ER)-beta-specific but not ER-alpha-specific agonist and was attenuated with loss of ER-beta expression, concordant with decreased E-cadherin expression. E-cadherin small-interfering RNA targeting eliminated Gen inhibition of Wnt-stimulated c-Myc expression and promoted Gen induction of basal c-Myc transcript levels and subsequent proliferation. Our studies identify E-cadherin as a Gen cellular target and demonstrate that the dichotomy in mammary epithelial response to Gen may be a function of cellular E-cadherin expression.