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

BackgroundOur 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.MethodsImmunohistochemistry 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.ResultsWe 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.ConclusionVav3 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.

[1]  B. Iacopetta,et al.  PIK3CA mutations in breast cancer are associated with poor outcome , 2006, Breast Cancer Research and Treatment.

[2]  V. Giguère,et al.  Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1. , 1999, Molecular cell.

[3]  Ji-ping Wang,et al.  Long-term Treatment with Tamoxifen Facilitates Translocation of Estrogen Receptor α out of the Nucleus and Enhances its Interaction with EGFR in MCF-7 Breast Cancer Cells , 2007 .

[4]  Rakesh Kumar,et al.  Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR , 2007, Nuclear receptor signaling.

[5]  Brian T Chait,et al.  The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. , 2002, Molecular cell.

[6]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Yi Zheng,et al.  AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner. , 2005, Molecular cancer research : MCR.

[8]  L. Wang,et al.  Distinct Role of Phosphatidylinositol 3-Kinase and Rho Family GTPases in Vav3-induced Cell Transformation, Cell Motility, and Morphological Changes* , 2002, The Journal of Biological Chemistry.

[9]  S. Yeh,et al.  From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Chi-Wai Wong,et al.  Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Revelo,et al.  Vav3 oncogene is overexpressed and regulates cell growth and androgen receptor activity in human prostate cancer. , 2006, Molecular endocrinology.

[12]  M. Barbacid,et al.  vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells. , 1989, The EMBO journal.

[13]  X. Bustelo.  Regulatory and Signaling Properties of the Vav Family , 2000, Molecular and Cellular Biology.

[14]  P. Dennis,et al.  Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. , 2002, Molecular cancer therapeutics.

[15]  H. Gronemeyer,et al.  The coactivator TIF2 contains three nuclear receptor‐binding motifs and mediates transactivation through CBP binding‐dependent and ‐independent pathways , 1998, The EMBO journal.

[16]  M. Tsai,et al.  Molecular Mechanisms of Androgen-Independent Growth of Human Prostate Cancer LNCaP-AI Cells1. , 1999, Endocrinology.

[17]  S Sommer,et al.  Estrogen Receptor and Breast Cancer , 2001, Cancer Drug Discovery and Development.

[18]  Xin-Yun Huang,et al.  Structural Basis for Relief of Autoinhibition of the Dbl Homology Domain of Proto-Oncogene Vav by Tyrosine Phosphorylation , 2000, Cell.

[19]  N. Varin‐Blank,et al.  Vav1 Is a Component of Transcriptionally Active Complexes , 2002, The Journal of experimental medicine.

[20]  John D. Welsh,et al.  Vav3 Mediates Receptor Protein Tyrosine Kinase Signaling, Regulates GTPase Activity, Modulates Cell Morphology, and Induces Cell Transformation , 2000, Molecular and Cellular Biology.

[21]  Ji-ping Wang,et al.  Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. , 2007, Cancer research.

[22]  J. Chen,et al.  The SRC family of nuclear receptor coactivators. , 2000, Gene.

[23]  C. Rochette-Egly.  Nuclear receptors: integration of multiple signalling pathways through phosphorylation. , 2003, Cellular signalling.

[24]  X. Bustelo,et al.  Tyrosine Phosphorylation Mediates Both Activation and Downmodulation of the Biological Activity of Vav , 2000, Molecular and Cellular Biology.

[25]  M. Hung,et al.  The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers. , 2005, Endocrine-related cancer.

[26]  J. Leal,et al.  Mice expressing myrAKT1 in the mammary gland develop carcinogen-induced ER-positive mammary tumors that mimic human breast cancer. , 2007, Carcinogenesis.

[27]  D. Edwards,et al.  Phosphorylation of MNAR Promotes Estrogen Activation of Phosphatidylinositol 3-Kinase , 2006, Molecular and Cellular Biology.

[28]  Brian T. Chait,et al.  E Protein Silencing by the Leukemogenic AML1-ETO Fusion Protein , 2004, Science.

[29]  W. Welshons,et al.  Estrogen receptors in membrane lipid rafts and signal transduction in breast cancer , 2006, Molecular and Cellular Endocrinology.

[30]  Frederick W. Alt,et al.  Vav Family Proteins Couple to Diverse Cell Surface Receptors , 2000, Molecular and Cellular Biology.

[31]  X. Bustelo.  Vav proteins, adaptors and cell signaling , 2001, Oncogene.

[32]  M. Beckmann,et al.  Gene Amplification and Expression of the Steroid Receptor Coactivator SRC3 (AIB1) in Sporadic Breast and Endometrial Carcinomas , 2001, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[33]  X. Bustelo,et al.  Biological and Regulatory Properties of Vav-3, a New Member of the Vav Family of Oncoproteins , 1999, Molecular and Cellular Biology.

[34]  Simak Ali,et al.  Endocrine-responsive breast cancer and strategies for combating resistance , 2002, Nature Reviews Cancer.

[35]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[36]  J. Downward,et al.  Mechanism of Epidermal Growth Factor Regulation of Vav2, a Guanine Nucleotide Exchange Factor for Rac* , 2003, The Journal of Biological Chemistry.

[37]  X. Bustelo,et al.  Structural Determinants for the Biological Activity of Vav Proteins* , 2002, The Journal of Biological Chemistry.

[38]  M. Tsai,et al.  Molecular mechanisms of androgen-independent growth of human prostate cancer LNCaP-AI cells. , 1999, Endocrinology.

[39]  S. Naber,et al.  Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. , 2007, Cancer research.

[40]  K. Burnstein,et al.  Vav3, a Rho GTPase guanine nucleotide exchange factor, increases during progression to androgen independence in prostate cancer cells and potentiates androgen receptor transcriptional activity. , 2006, Molecular endocrinology.

[41]  J. Engelman,et al.  Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. , 2005, Cancer research.

[42]  G. Mills,et al.  The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. , 2001, Seminars in oncology.

[43]  Anupama E. Gururaj,et al.  Novel Mechanisms of Resistance to Endocrine Therapy: Genomic and Nongenomic Considerations , 2006, Clinical Cancer Research.