Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer

Background: 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 (ER alpha)-mediated signaling axis. Methods: 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 ERa activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERa activation. Finally, the interaction of Vav3 and ERa was assessed by GST pull-down analysis. Results: We found that Vav3 was overexpressed in 81% of human breast cancer specimens, particularly in poorly differentiated lesions. Vav3 activated ER alpha partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERa activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERa. Consistent with its function for AR, the DH domain of Vav3 was essential for ER alpha activation. Conclusion: Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERa and enhances ERa activity. These findings suggest that Vav3 overexpression may aberrantly enhance ER alpha-mediated signaling axis and play a role in breast cancer development and/or progression.