Prostate cancer is the most common cancer in men and is the second leading cause of cancer deaths in men in the United States. Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer, especially issues related to metastasis and resistance to androgen ablation therapy, remain relatively unknown in comparison with other common cancers. The PTEN tumor suppressor gene is deleted in 30% of primary prostate cancers and 63% of prostate metastatic lesions, placing PTEN loss among the most common genetic alterations in human prostate cancers. The long term objective of this application is to understand the molecular mechanisms underlying prostate tumor initiation, progression, metastasis, and hormone resistance, and to identify new targets for drug development as well as new biomarkers for monitoring treatment, using our genetically defined murine Pten conditional knock-out model.
Aim 1 will focus on characterization of the course of the disease in this model and on the location and the cell types associated with prostate cancer metastasis. """"""""Reporter mice"""""""" have been generated for this purpose for in vivo, non-invasive imaging and for tracking specific cell types during tumor progression and metastasis. We will directly test the hypothesis that prostate cancer may arise from dysregulated stem/progenitor cells. Since the murine Pten prostate cancer model is the only model currently available in which the primary tumorigenic lesion is not regulated by androgen, Aim 2 will dissect hormone resistant mechanisms and identify the cellular origin of hormone refractory prostate cancer. Finally, tumor tissues and cell lines will be used for genome-wide microarray analyses and comparative genome hybridization analyses. This dataset will be compared with similar datasets from human prostate cancers to identify key molecular events in prostate cancer progression, metastasis, and hormone resistance. Candidate genes will be further evaluated biochemically and genetically for their contributions to prostate cancer development. Although focused on prostate cancer, the studies outlined here and the mechanisms elucidated in this proposal will be broadly relevant to cancers associated with PTEN loss in general, since PTEN is expressed in all cell types in our body and PTEN mutations are observed in many human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107166-03
Application #
7032347
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mohla, Suresh
Project Start
2004-04-07
Project End
2009-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$306,727
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ruscetti, M; Dadashian, E L; Guo, W et al. (2016) HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35:3781-95
Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L et al. (2015) Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells during Prostate Cancer Metastasis. Cancer Res 75:2749-59
Garcia, Alejandro J; Ruscetti, Marcus; Arenzana, Teresita L et al. (2014) Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression. Mol Cell Biol 34:2017-28
Hübner, Anette; Mulholland, David J; Standen, Claire L et al. (2012) JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate. Proc Natl Acad Sci U S A 109:12046-51
Jiao, Jing; Hindoyan, Antreas; Wang, Shunyou et al. (2012) Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells. PLoS One 7:e42564
Mulholland, David J; Kobayashi, Naoko; Ruscetti, Marcus et al. (2012) Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res 72:1878-89
Tran, Linh M; Chang, Chun-Ju; Plaisier, Seema et al. (2012) Determining PTEN functional status by network component deduced transcription factor activities. PLoS One 7:e31053
Hill, Reginald; Li, Yunfeng; Tran, Linh M et al. (2012) Cell intrinsic role of COX-2 in pancreatic cancer development. Mol Cancer Ther 11:2127-37
Mulholland, David J; Tran, Linh M; Li, Yunfeng et al. (2011) Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19:792-804
Lukacs, Rita U; Memarzadeh, Sanaz; Wu, Hong et al. (2010) Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell 7:682-93

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