The overall objective of this proposal is to investigate the role of the androgen receptor (AR) in prostate cancer metastasis. Prostate cancer is the second leading cause of cancer-related death among men in the United States. Androgen action and the functional status of the AR are believed to be the important mediators of prostate cancer development. Although androgen/AR is known to promote growth of androgen-dependent prostate tumors, its function in tumor metastasis is unclear at present. A preliminary study has been made in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models of prostate cancer and discovered that ablation of the AR in prostate epithelium resulted in development of larger pelvic lymph node (PLN) metastatic tumors and higher numbers of liver metastatic foci, suggesting that AR might function as a suppressor of prostate tumor metastasis. Therefore, the proposed studies will use various ARKO models of TRAMP mice and human prostate cancer cell lines with different AR expression to investigate the suppressor role of AR in prostate tumor metastasis. Initially prostate epithelium-specific (pes) AR knockout (ARKO) (Aim 1) and inducible ARKO TRAMP mice (Aim 2) will be generated to study the effect of pes-ARKO and induction of ARKO, after prostate tumors have developed, on PLN metastatic tumor formation and growth as well as the expression levels of various metastasis-related genes. Subsequently, the effect of suppressing AR expression (with AR-specific RNA interference) in AR-positive and restoring AR expression (with functional AR cDNA) in AR-negative PLN tumor cells and various human prostate cancer cell lines (Aim 3) on their invasive properties and expression levels of metastasis-related genes will be studied in vitro as well as in bone xenografts in SCID mice. Finally, the molecular mechanisms through which AR regulates the expression levels of various metastasis-related genes will be studied (Aim 4). Therefore, the success of this application undoubtedly will uncover an alterative role of the AR as a metastasis suppressor during prostate cancer progression. The establishment of the AR function as a metastasis suppressor and understanding of how it regulates tumor metastasis-related genes, should lead to new concepts of treatment modality and molecular targeting for prostate cancer therapy. Project Narrative: Loss of Androgen Receptor Promotes Metastatic Cancer. We will study the loss of androgen receptor in prostate epithelium and the influence of this loss on prostatic metastatic tumor invasion. The success of this application undoubtedly will uncover an alterative role of the androgen receptor as a metastasis suppressor during prostate cancer progression. The establishment of the androgen receptor function as a metastasis suppressor and understanding of how it regulates tumor metastasis-related genes, should lead to new concepts of treatments and molecular targets for prostate cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122840-05
Application #
8099646
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2007-09-21
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$283,822
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Qiu, Xiaofu; Zhu, Jin; Sun, Yin et al. (2015) TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGF?R2/p-Smad3 signals. Oncotarget 6:15397-409
Ding, Xianfan; Yang, Dong-Rong; Xia, Liqun et al. (2015) Targeting TR4 nuclear receptor suppresses prostate cancer invasion via reduction of infiltrating macrophages with alteration of the TIMP-1/MMP2/MMP9 signals. Mol Cancer 14:16
Luo, Jie; Lee, Soo Ok; Cui, Yun et al. (2015) Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2?/androgen receptor signals. Oncotarget 6:27555-65
Zhu, Jin; Yang, Dong-Rong; Sun, Yin et al. (2015) TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression. Mol Cancer Ther 14:1445-53
Luo, J; Ok Lee, S; Liang, L et al. (2014) Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling. Oncogene 33:2768-78
Zhu, Guodong; Liang, Liang; Li, Lei et al. (2014) The expression and evaluation of androgen receptor in human renal cell carcinoma. Urology 83:510.e19-24
Wang, Xiaohai; Lee, Soo Ok; Xia, Shujie et al. (2013) Endothelial cells enhance prostate cancer metastasis via IL-6?androgen receptor?TGF-??MMP-9 signals. Mol Cancer Ther 12:1026-37
Huang, Chiung-Kuei; Tsai, Meng-Yin; Luo, Jie et al. (2013) Suppression of androgen receptor enhances the self-renewal of mesenchymal stem cells through elevated expression of EGFR. Biochim Biophys Acta 1833:1222-34
Yu, Shengqiang; Xia, Shujie; Yang, Diandong et al. (2013) Androgen receptor in human prostate cancer-associated fibroblasts promotes prostate cancer epithelial cell growth and invasion. Med Oncol 30:674

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