Mammary cancer promotion by ovarian hormones involves IGFR/AKT/mTOR signaling
Mammary cancer promotion by ovarian hormones involves IGFR/AKT/mTOR signaling
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DOI：
10.1016/j.steroids.2012.03.009
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发表时间：
2012-06-01
期刊：
影响因子：
2.7
通讯作者：
Rajkumar, Lakshmanaswamy
中科院分区：
文献类型：
--
作者：
Arumugam, Arunkumar;Parada, Jacqueline;Rajkumar, Lakshmanaswamy
在之前的一项研究中，我们观察到n -甲基-n -亚硝基脲（MNU）诱导的乳腺病变在外源性雌二醇(E)和孕酮(P)的作用下被促进为显性乳腺癌。本研究的目的是确定在激素促进乳腺癌发生和持续激活负责肿瘤生长的分子途径过程中发生的早期分子事件。7周龄雌性哥本哈根（COP）大鼠对MNU诱导的乳腺癌具有抗性，腹腔注射单剂量MNU （50 mg/kg体重）。致癌物给药6周后，分别于第15周和第43周处死大鼠，取乳腺病变和肿瘤组织，并进行分子分析。定量RT-PCR实验显示，乳腺病变和肿瘤组织中Igfr、Grb2、Sos1、Shc1 mRNA表达升高。免疫印迹数据还显示乳腺病变和肿瘤中IGFR、GRB2和SHC1蛋白水平升高，这与它们各自的RT-PCR数据相关。AKT和ERK1/2的激活在E + P治疗的乳腺病变和肿瘤中上调。mTOR通路蛋白的分子分析显示，在激素治疗的肿瘤中，p70S6K和4EBP1的磷酸化增加，表明mTOR信号的激活。E + P处理降低BAX蛋白表达，上调BCL2表达，下调活性caspase 3和8。综上所述，这些数据表明卵巢激素通过增强IGFR和Akt/mTOR信号以及抑制凋亡刺激来促进乳腺肿瘤的病变。(C) 2012爱思唯尔公司版权所有。
In a previous study, we observed that N-methyl-N-nitrosourea (MNU)-induced mammary lesions are promoted to overt mammary cancers by exogenous administration of estradiol (E) and progesterone (P). The purpose of the present study was to identify the early molecular events occurring during the hormonal promotion of mammary carcinogenesis and persistent activation of molecular pathways responsible for tumor growth. Seven-week-old female Copenhagen (COP) rats, which are resistant to MNU-induced mammary carcinogenesis, were intraperitoneally administered a single dose of MNU (50 mg/kg body weight). Six weeks after carcinogen administration, the rats were treated with E + P. killed at 15th week and 43rd week to obtain mammary lesions and tumor tissues and the molecular analysis were performed. Quantitative RT-PCR experiments showed increased mRNA expression of Igfr, Grb2, Sos1, and Shc1 in mammary lesions and tumors. Immunoblot data also showed increased protein levels of IGFR, GRB2 and SHC1 in mammary lesions and tumors, which is in correlation with their respective RT-PCR data. Activation of AKT and ERK1/2 were up regulated in E + P treated mammary lesions and tumors. Molecular analysis of mTOR pathway proteins revealed increased phosphorylation of p70S6K and 4EBP1 in the hormone treated tumors indicating the activation of mTOR signaling. E + P treatment reduced the protein expression of BAX and increased BCL2 expression along with down regulation of active caspase 3 and 8. Together, these data demonstrate that ovarian hormones promote the lesions to mammary tumors by enhancing IGFR and Akt/mTOR signaling along with inhibition of apoptotic stimuli. (C) 2012 Elsevier Inc. All rights reserved.