Elevated androgen receptor (AR) activity and PI3K-Akt signaling are involved in prostate cancer development and progression. The mechanisms responsible for elevation of these two key signaling pathways in prostate cancer, however, have not fully elucidated. We found that Vav3 oncogene, a quanine nucleotide exchange factor (GEF) for Rac/Rho GTPases, is overexpressed in androgen-independent prostate cancer cells and in 32% of human prostate cancer. Further analysis revealed that Vav3 stimulates growth of prostate cancer cells, interacts with AR via the DH domain, and activates AR as a coactivator. Vav3, as a signal transducer, also upregulates PI3K-Akt signaling leading to AR activation. Furthermore, targeted overexpression of Vav3 in the prostate epithelium induces prostatic intraepithelial neoplasia (mPIN) in young adult mice as early as two months old. We hypothesize that overexpression of Vav3 inappropriately activates AR and promotes prostate cancer development and that further elevated Vav3 activity stimulates prostate cancer progression to the androgen-independent status.
Three Specific Aims are proposed to test the hypothesis.
Specific Aim 1 : To determine the role of Vav3 overexpression in prostate cancer development and progression to the androgen-independent status in mouse prostate cancer models. We will investigate whether forced overexpression of Vav3 stimulates androgen-independent growth in prostate tumor and whether targeted overexpression of Vav3 in the prostate epithelium induces prostate cancer development and stimulates progression to the androgen-independent status in transgenic mice.
Specific Aim 2 : To elucidate the signaling pathways of Vav3 in prostate cancer. We will determine the underlying molecular mechanisms of Vav3 coactivation for AR and Vav3 signaling via the conventional Vav3-Rho-PI3K-Akt pathway leading AR activation in prostate cancer cells. We will also build up the whole Vav3-mediated signaling pathways that connect extracellular stimuli to AR signaling axis as well as cell growth and survival pathway by GST-pull down and Mass Spectrometry-based proteomics analysis.
Specific Aim 3 : To associate Vav3 overexpression with Gleason score, pathologic stage, PI3K-Akt signaling, and androgen-independent status in human prostate cancers. Once completed, these studies from the preclinical mouse model to the clinical study in human prostate cancer specimens will further our understanding of the mechanisms of prostate cancer development and its androgen-independent growth and provide targets and animal models for the rational development of novel therapies against prostate cancer. ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA119935-01A2
Application #
7259778
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
2007-08-28
Project End
2012-05-31
Budget Start
2007-08-28
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$266,322
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Dong, Zhongyun; Meller, Jaroslaw; Succop, Paul et al. (2014) Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells. Int J Oncol 45:978-84
Oleksowicz, Leslie; Liu, Yin; Bracken, R Bruce et al. (2012) Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer. Prostate 72:1140-9
Dong, Zhongyun; Liu, Yin; Levin, Linda et al. (2011) Vav3 oncogene is involved in regulation of secretory phospholipase A2-IIa expression in prostate cancer. Oncol Rep 25:1511-6
Kupert, Elena; Anderson, Marshall; Liu, Yin et al. (2011) Plasma secretory phospholipase A2-IIa as a potential biomarker for lung cancer in patients with solitary pulmonary nodules. BMC Cancer 11:513
Liu, Yin; Wu, Xiaoyang; Dong, Zhongyun et al. (2010) The molecular mechanism of Vav3 oncogene on upregulation of androgen receptor activity in prostate cancer cells. Int J Oncol 36:623-33
Dong, Zhongyun; Liu, Yin; Scott, Kieran F et al. (2010) Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer. Carcinogenesis 31:1948-55
Lee, Kiwon; Liu, Yin; Mo, Jun Qin et al. (2008) Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer. BMC Cancer 8:158
Liu, Yin; Mo, Jun Qin; Hu, Qiande et al. (2008) Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer. Cancer Res 68:6396-406