Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer.
Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer.
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DOI：
10.1186/1471-2407-8-158
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发表时间：
2008-06-02
期刊：
影响因子：
3.8
通讯作者：
Lu, Shan
中科院分区：
文献类型：
--
作者：
Lee, Kiwon;Liu, Yin;Mo, Jun Qin;Zhang, Jinsong;Dong, Zhongyun;Lu, Shan
我们先前的研究发现，Vav3癌基因在人前列腺癌中过表达，激活雄激素受体，并刺激前列腺癌细胞的生长。本研究旨在探讨Vav3癌基因在人乳腺癌中的作用及其对雌激素受体a(ERα)介导的信号轴的影响。采用免疫组织化学方法检测43例乳腺癌标本中Vav3蛋白的表达水平，并用免疫印迹法检测人乳腺癌细胞株Vav3蛋白的表达。通过siRNA抑制Vav3的表达来确定Vav3对乳腺癌细胞生长的影响。荧光素酶报告基因分析检测Vav3在ERα激活中的作用。对Vav3蛋白进行缺失突变分析，定位参与ERα激活的功能结构域。最后，通过GST下拉分析评估Vav3与ERα的相互作用。我们发现Vav3在81%的人类乳腺癌标本中过表达，特别是在低分化病变中。Vav3通过PI3K-α信号通路部分激活ER-Akt，促进乳腺癌细胞生长。Vav3还增强了乳腺癌细胞生长的表皮生长因子活性和ERα的激活。更有趣的是，我们发现Vav3与ERα形成复合体。与其对AR的功能一致，Vav3的水解域是ERα激活所必需的。Vav3癌基因在人类乳腺癌中过表达。Vav3与ERα形成络合物，增强ERα活性。这些结果提示，Vav3过表达可能异常增强ER-α介导的信号轴，并在乳腺癌的发生和/或进展中发挥作用。
Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERα)-mediated signaling axis. Immunohistochemistry analysis was performed in 43 breast cancer specimens and western blot analysis was used for human breast cancer cell lines to determine the expression level of Vav3 protein. The impact of Vav3 on breast cancer cell growth was determined by siRNA knockdown of Vav3 expression. The role of Vav3 in ERα activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERα activation. Finally, the interaction of Vav3 and ERα was assessed by GST pull-down analysis. We found that Vav3 was overexpressed in 81% of human breast cancer specimens, particularly in poorly differentiated lesions. Vav3 activated ERα partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERα activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERα. Consistent with its function for AR, the DH domain of Vav3 was essential for ERα activation. Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERα and enhances ERα activity. These findings suggest that Vav3 overexpression may aberrantly enhance ERα-mediated signaling axis and play a role in breast cancer development and/or progression.
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