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 (ERalpha)-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 ERalpha activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERalpha activation. Finally, the interaction of Vav3 and ERalpha 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 ERalpha partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERalpha activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERalpha. Consistent with its function for AR, the DH domain of Vav3 was essential for ERalpha activation.


CONCLUSIONS
Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERalpha and enhances ERalpha activity. These findings suggest that Vav3 overexpression may aberrantly enhance ERalpha-mediated signaling axis and play a role in breast cancer development and/or progression.
Lee
Kiwon
K
Department of Pathology, University of Cincinnati College of Medicine, 2120 E, Galbraith Road, Cincinnati, OH 45237, USA. leeko@UCMAIL.UC.EDU
Liu
Yin
Y
Mo
Jun Qin
JQ
Zhang
Jinsong
J
Dong
Zhongyun
Z
Lu
Shan
S
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D020662:Guanine Nucleotide Exchange Factors; D051567:Proto-Oncogene Proteins c-vav; C496621:VAV3 protein, human; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt