The androgen receptor (AR) is a nuclear hormone receptor and promotes prostate cancer growth through activation of its downstream target genes. Although the targets of AR activation remain unclear, they are believed to be critical for cellular proliferation because most prostate cancers express the AR and are androgen-dependent. That depletion of androgens results in significant regression of prostate tumors was demonstrated in 1941 by Charles Huggins and Clarence Hodges and heralded what is now the ubiquitous strategy of androgen deprivation therapy to treat prostate cancer. Unfortunately, within two to three years after initiating therapy, most patients invariably relapse with a more aggressive form of prostate cancer, known as castration resistant prostate cancer (CRPC). There is no effective treatment option for CRPC, which has mainly contributed to the mortality of the disease. AR gene amplification has been observed in almost one-third of prostate cancers after androgen ablation therapy. Global gene expression profiling shows AR as the only gene to be consistently up-regulated in CRPC, implicating the significance of AR in disease progression. We and others have provided multiple lines of evidence demonstrating a critical role of AR in ligand-independent cell growth, implying that androgen- independent cells may still be AR dependent and that the AR can be used as a possible therapeutic target. However, the precise role of the AR in prostate cancer progression and CRPC development is still unclear. One of the main reasons for the limited progress is the lack of appropriate animal models that can be used to evaluate ligand independent AR action during the course of disease progression. To address this, we have developed several novel mouse models that allow us to investigate the progression of prostate cancer that is androgen independent but AR-dependent, mimicking what typically occurs in most human prostate cancers. In this competing renewal, we propose three different but integrated specific aims to directly test our central hypothesis that abnormal activation of AR dysregulates cell differentiation and proliferation that directly contribute to prostate cancer initiation and progression.
Three specific aims are proposed in this application to address three different but related questions: 1) how abnormal activation of AR promotes tumor progression? 2) does aberrant activation of AR induce expression and activation of ETS proteins in promoting prostate cancer progression? 3) what are the molecular mechanisms underlying aberrant activation of AR in prostate cancer progression and CRPC development?

Public Health Relevance

Three specific aims are proposed in this revised competing renewal to investigate androgen signaling in prostate cancer progression and castration resistant prostate cancer development. Data generated from this study should lead to the development of new therapeutic strategies for treating advanced prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070297-19
Application #
9197890
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Woodhouse, Elizabeth
Project Start
2016-05-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
19
Fiscal Year
2017
Total Cost
$1
Indirect Cost
$125,637
Name
Beckman Research Institute/City of Hope
Department
Type
Research Institutes
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Lee, S H; Luong, R; Johnson, D T et al. (2016) Androgen signaling is a confounding factor for β-catenin-mediated prostate tumorigenesis. Oncogene 35:702-14
Johnson, Daniel T; Hooker, Erika; Luong, Richard et al. (2016) Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice. PLoS One 11:e0148851
Lee, Suk Hyung; Johnson, Daniel; Luong, Richard et al. (2015) Crosstalking between androgen and PI3K/AKT signaling pathways in prostate cancer cells. J Biol Chem 290:2759-68
Lee, Suk Hyung; Johnson, Daniel T; Luong, Richard et al. (2015) Wnt/β-Catenin-Responsive Cells in Prostatic Development and Regeneration. Stem Cells 33:3356-67
Johnson, Daniel T; Luong, Richard; Lee, Suk Hyung et al. (2013) Deletion of leucine zipper tumor suppressor 2 (Lzts2) increases susceptibility to tumor development. J Biol Chem 288:3727-38
Lee, Suk Hyung; Zhu, Chunfang; Peng, Yue et al. (2013) Identification of a novel role of ZMIZ2 protein in regulating the activity of the Wnt/β-catenin signaling pathway. J Biol Chem 288:35913-24
Kwak, Mi Kyung; Johnson, Daniel T; Zhu, Chunfang et al. (2013) Conditional deletion of the Pten gene in the mouse prostate induces prostatic intraepithelial neoplasms at early ages but a slow progression to prostate tumors. PLoS One 8:e53476
Peng, Yue; Clark, Curtis; Luong, Richard et al. (2011) The leucine zipper putative tumor suppressor 2 protein LZTS2 regulates kidney development. J Biol Chem 286:40331-42
Zhu, Chunfang; Luong, Richard; Zhuo, Ming et al. (2011) Conditional expression of the androgen receptor induces oncogenic transformation of the mouse prostate. J Biol Chem 286:33478-88
Li, Xiaomeng; Zhu, Chunfang; Tu, William H et al. (2011) ZMIZ1 preferably enhances the transcriptional activity of androgen receptor with short polyglutamine tract. PLoS One 6:e25040

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