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

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.Vav3 oncogene, a quanine nucleotide exchange factor (GEF) for Rho family GTPases, belongs to Vav family proteins. The three mammalian Vav proteins (Vav1, Vav2, and Vav3) differ in their tissue distribution. Vav1 is primarily expressed in hematopoietic cells, while Vav2 and Vav3 are more ubiquitously expressed [1,2]. Vav proteins contain multiple function motifs and are involved in various cellular signaling processes, including cytoskeleton organization, calcium influx, phagocytosis, and cell transformation [3]. Vav proteins share a common structure, including a N-terminal calponin homology (CH) domain involved in Ca+2 mobilization and transforming activity, an acidic domain (AD)