Like most other cancers, prostate carcinogenesis involves a multistep progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. During the metastatic phase of this illness tumor cells often lose cell-cell contact and possess a more aggressive growth phenotype. Observations from androgen ablation treatment of prostate cancer have shown that the androgen-signaling pathway is important in the growth and progression of prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). Loss of E-cadherin from the cell membrane is frequently observed in the late stages of prostate cancer, which is closely associated with the increased invasive behavior of tumor cells and a poor clinical outcome. Beta-catenin, normally localized in the cell membrane, in the cytoplasm and in the nucleus, plays dual roles in intercellular adhesion and signal transduction. Recently, we demonstrated a specific protein-protein interaction between beta-catenin and AR. Unlike the steroid receptor cofactor 1 (SRC1), beta-catenin selectively binds to AR in a ligand-dependent manner, but does not bind to other steroid hormone receptors. The interaction domains between AR and beta-catenin are mapped to the ligand binding domain of AR and the N-terminus and central region spanning the armadillo repeats 1-6 of beta-catenin. Through this specific interaction, beta-catenin augments the ligand-dependent activity of AR in prostate cancer cells. These data suggest that beta-catenin is a coactivator of the AR and may play a critical role in AR mediated cell growth and survival. Based on the evidence that loss of E-cadherin expression is frequently observed in the advanced stages of prostate cancer, beta-catenin is a coactivator of the AR and may play a critical role in AR mediated cell growth and survival. Our major objective in this proposal is to further characterize the interaction between AR and beta-catenin in order to understand the biological roles of beta-catenin and its crosstalk with androgen signaling in the tumorigenesis of prostate cancer. Ultimately, we wish to identify the key regions for the interaction (Aim 1), determine the biological roles of beta-catenin and its interaction with AR in prostate cancer cells (Aim 2), and define physiological significance of beta-catenin and its regulation in the pathogenesis of prostate cancer (Aim 3). The long-term goal of this study is to identify new steps that can be targeted for the treatment of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK061002-01A1
Application #
6572937
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Margolis, Ronald N
Project Start
2003-02-01
Project End
2007-12-31
Budget Start
2003-02-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$336,715
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Wang, Xiaowan; Song, Runmin; Lu, Wenliang et al. (2017) YXQN Reduces Alzheimer's Disease-Like Pathology and Cognitive Decline in APPswePS1dE9 Transgenic Mice. Front Aging Neurosci 9:157
Yu, Eun-Jeong; Hooker, Erika; Johnson, Daniel T et al. (2017) LZTS2 and PTEN collaboratively regulate ß-catenin in prostatic tumorigenesis. PLoS One 12:e0174357
Peng, Yue; Lee, Jane; Zhu, Chunfang et al. (2010) A novel role for protein inhibitor of activated STAT (PIAS) proteins in modulating the activity of Zimp7, a novel PIAS-like protein, in androgen receptor-mediated transcription. J Biol Chem 285:11465-75
Lee, Jane; Beliakoff, Jason; Sun, Zijie (2007) The novel PIAS-like protein hZimp10 is a transcriptional co-activator of the p53 tumor suppressor. Nucleic Acids Res 35:4523-34
Li, Tzu-Huey; Zhao, Hongjuan; Peng, Yue et al. (2007) A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells. Nucleic Acids Res 35:2767-76
Verras, Meletios; Lee, Jane; Xue, Hui et al. (2007) The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res 67:967-75
Li, Xiaomeng; Thyssen, Gregory; Beliakoff, Jason et al. (2006) The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity. J Biol Chem 281:23748-56
Verras, Meletios; Sun, Zijie (2006) Roles and regulation of Wnt signaling and beta-catenin in prostate cancer. Cancer Lett 237:22-32
Thyssen, Gregory; Li, Tzu-Huey; Lehmann, Lynn et al. (2006) LZTS2 is a novel beta-catenin-interacting protein and regulates the nuclear export of beta-catenin. Mol Cell Biol 26:8857-67
Verras, Meletios; Sun, Zijie (2005) Beta-catenin is involved in insulin-like growth factor 1-mediated transactivation of the androgen receptor. Mol Endocrinol 19:391-8

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