European Journal of Cancer Prevention the Official Journal of the European Cancer Prevention Organisation, 2010, 19(2):110-9.

Prepubertal genistein exposure affects erbB2/Akt signal and reduces rat mammary tumorigenesis

Jun-Hua Peng, Rong-Li Xue, et al

Department of Nutrition and Food Hygiene, The Third Military Medical University, Chongqing, China; et al

Breast cancer is the most common malignancy in women worldwide and pharmaceutical agents have therapeutic and preventive effects in breast cancer. The human epidermal growth factor receptor 2/neu is one of the most important oncogenes in human breast cancer. Prepubertal exposure to endogenous estradiol and a phytoestrogen, genistein (Gen), has been shown to reduce future breast cancer risk. Gen downregulates tyrosine kinase regulated protein expression and reduces prostate cancer. In this study, the effects of prepubertal exposure to Gen on rat mammary carcinogenesis and the erbB2/Akt signal pathway were investigated. Prepubertal female Sprague-Dawley rats were daily exposed to Gen at 125 mg/kg (Gen-1) and 500 mg/kg (Gen-5) from postnatal days 22-28. Subsequently, the rats were given a single dose of 100 mg/kg 7.12-dimethylbenz [a] anthracene on postnatal day 42 to induce mammary tumor. The mRNA expression of erbB2 and amplified in breast cancer 1 (AIB1) was detected by reverse transcription-polymerase chain reaction. The protein levels of proliferating cell nuclear antigen (PCNA), erbB2, phosphotyrosine protein, Akt, and p-Akt were detected by immunohistochemistry and Western blotting. The activity of protein tyrosine kinase (PTK) was detected by liquid scintillation counting. The percentage of rats with mammary tumors in breast cancer model (BCM), Gen-1, and Gen-5 was 71.43, 52.38, and 33.34%, respectively. The incidence of 7.12-dimethylbenz [a] anthracene-induced mammary tumors significantly decreased in Gen-5 compared with that in BCM. The mRNA levels of AIB1 and erbB2 and the protein levels of erbB2, p-Akt, and PCNA protein expression were downregulated for a long time in the mammary tumors in Gen-5 groups. The activity of PTK was also decreased for a long time. However, the total Akt protein expression did not change significantly among BCM, Gen-1, and Gen-5. Prepubertal exposure of Sprague-Dawley female rats to 500 mg/kg Gen can reduce later breast cancer risk and its protective effect is associated with persistent downregulation of the expression of erbB2, p-Akt, AIB1, and PCNA and with low PTK activity in the mammary tumor. Our results suggest that erbB2/Akt signaling plays a role in tumor formation and targeting erbB2/Akt signaling with prepubertal exposure to Gen may provide greater efficacy to the current therapies used to treat tumors.

英国《欧洲癌症预防》，2010年8月

青春期前金雀异黄素的暴露会影响 erbB2/Akt 信号和减少大鼠乳腺肿瘤生成

彭俊华，薛荣丽等

中国重庆第三军医大学营养与食品卫生学院等

乳腺癌是全世界妇女最常见的恶性肿瘤并且医药制剂可以预防和治疗乳腺癌。人体表皮生长因子受体 2/神经鞘在人体乳腺癌中是最重要的致癌基因之一。青春期前暴露于内源性雌二醇和一种植物雌激素，金雀异黄素 （Gen）中，已被证明可以降低未来患乳腺癌的风险。Gen 下调了酪氨酸激酶调控蛋白的表达，降低前列腺癌。在此研究中，探究了青春期前暴露于Gen对大鼠乳腺细胞癌变和 erbB2/Akt 信号通路的影响。自出生后青春期前雌性大鼠每天被暴露在 125 mg/kg (Gen-1) 和 500 mg/kg (Gen-5)共 22-28天。随后，在出生后42天给予小鼠 100 mg/kg剂量的 7.12-二甲基苯并 [a] 蒽来诱发乳腺肿瘤。erbB2的mRNA 表达和在乳腺癌1 (AIB1) 中的扩增通过 逆转录-聚合酶链反应检测到。采用免疫组化和免疫印迹检测增殖细胞核抗原(PCNA)的蛋白质水平，erbB2，磷酸化酪氨酸蛋白，Akt，和 p-Akt。通过液体闪烁计数仪来检测蛋白酪氨酸激酶 (PTK) 的活性。患有乳腺癌的老鼠比例在乳腺癌模型 (BCM)，Gen-1 和Gen-5中分别为71.43， 52.38 和 33.34%。7.12-二甲基苯并 [a] 蒽诱发乳腺癌的比率在Gen-5组明显低于BCM组。AIB1和erbB2的mRNA 水平以及erbB2的蛋白质水平，p-Akt和 PCNA的 蛋白表达在Gen-5 组乳腺肿瘤中下调了很长时间。PTK 活性也降低了很长时间。然而，总的 Akt 蛋白表达在BCM，Gen-1 和Gen- 5组均没有明显变化。雌性大鼠在青春期前暴露于 500 mg/kg的Gen可以减少以后患乳腺癌的风险，并且其保护作用与erbB2，p-Akt、 AIB1和PCNA的持续下调表达伴随着乳腺肿瘤较低 PTK 活性有关。我们的结果表明 erbB2/Akt 信号转导在肿瘤形成中发挥作用，并且针对 erbB2/Akt 信号在青春期前暴露于Gen中的方法相比于目前所使用肿瘤疗法可能会提供更大的疗效。