A number of genetic aberrations that naturally associate with human prostate cancer has been identified. To study the disease mechanism, one approach is to apply this knowledge rationally in modeling prostate cancer in mice in order to recapitulate the natural history and clinical course of the disease. Clues obtained from the models could then be examined for their correlation or validity using appropriate human prostatic cell systems and lesions. Such integrated and parallel investigations are likely to yield new insights into the pathogenesis of this common disease. The work we have initiated or planned considers three specific genetic aberrations, which are activation of a growth factor, FGF8, isoform b; deficiency in retinoid receptor function; and inactivation of Pten tumor suppressor gene. The premise of this focus is on the recognition of genetic synergy in signaling between these aberrations that converges to drive cell proliferation and survival. We hypothesize that successive development of increasingly complex mouse models with respect to these aberrations should provide significant opportunities for studying the molecular mechanisms that lead to genesis and progression of prostate cancer. Based on our findings of histopathological defects that resemble early stages of prostate cancer in single models from FGF8 overexpression or RXRalpha receptor inactivation in the prostate epithelium, our first aim is to determine the validity of the FGF8b; RXRalpha compound mutant mice for the study of prostate tumorigenesis. In the second aim, we propose to characterize the altered prostatic lobe-specific secretory proteins in the individual single models in terms of signaling defects or pathogenesis, and define the basis for the observed stromal proliferation in the FGF8b or compound model. Finally, the third aim concerns incorporation of Pten deficiency to derive triple mutant mice, likely to progress beyond adenocarcinoma, for the analyses of candidate signaling molecules and prostate lobe-specific gene expression changes in progression to androgen-dependent cancer, and potentially further to metastatic lesions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-CPA (02))
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Mohla, Suresh
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University of Southern California
Schools of Medicine
Los Angeles
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Liang, Mengmeng; Adisetiyo, Helty; Li, Xiuqing et al. (2015) Identification of Androgen Receptor Splice Variants in the Pten Deficient Murine Prostate Cancer Model. PLoS One 10:e0131232
Adisetiyo, Helty; Liang, Mengmeng; Liao, Chun-Peng et al. (2014) Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts. J Cell Physiol 229:1170-6
Geary, Lauren A; Nash, Kevin A; Adisetiyo, Helty et al. (2014) CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features. Mol Cancer Res 12:607-21
Adisetiyo, Helty; Liang, Mengmeng; Liao, Chun-Peng et al. (2013) Loss of survivin in the prostate epithelium impedes carcinogenesis in a mouse model of prostate adenocarcinoma. PLoS One 8:e69484
Pham, Linda Kim; Liang, Mengmeng; Adisetiyo, Helty A et al. (2013) Contextual effect of repression of bone morphogenetic protein activity in prostate cancer. Endocr Relat Cancer 20:861-74
Wu, Xinyu; Gong, Shiaoching; Roy-Burman, Pradip et al. (2013) Current mouse and cell models in prostate cancer research. Endocr Relat Cancer 20:R155-70
Mao, Gloria E; Harris, Diane M; Moro, Aune et al. (2012) A joint effect of new Western diet and retinoid X receptor ? prostate-specific knockout with development of high-grade prostatic intraepithelial neoplasia in mice--a preliminary study. Prostate 72:1052-9
Garlick, David S; Li, Jing; Sansoucy, Brian et al. (2012) ?(V)?(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma. Am J Transl Res 4:165-74
Ting, Man-Chun; Liao, Chun-Peng; Yan, Chunli et al. (2012) An enhancer from the 8q24 prostate cancer risk region is sufficient to direct reporter gene expression to a subset of prostate stem-like epithelial cells in transgenic mice. Dis Model Mech 5:366-74
Goel, Hira Lal; Chang, Cheng; Pursell, Bryan et al. (2012) VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer. Cancer Discov 2:906-21

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