Circulating vitamin D levels are inversely associated with prostate cancer risk and supplementation with vitamin D for prostate cancer prevention has been proposed. We recently developed a mouse model of adult prostate progenitor/stem cells (PrP/SC). The adult tissue specific stem cell may be an important target for chemoprevention. We have interrogated the effects of the active metabolite of vitamin D, 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3], on the PrP/SC. 1,25(OH)2D3 blocks proliferation, induces cell cycle arrest, and increases expression of cyclin-dependent kinase inhibitors p21 and p27. Our data suggest that 1,25(OH)2D3 promotes differentiation of the PrP/SC. Consistent with prodifferentiation we observe increased androgen receptor (AR) expression in 1,25(OH)2D3-treated PrP/SC. To identify novel targets of vitamin D receptor transcriptional activity and to assess global gene expression changes we probed gene expression arrays with RNA from 1,25(OH)2D3-treated PrP/SC. We identified a signaling pathway that is both necessary and sufficient for 1,25(OH)2D3 antiproliferative actions on the PrP/SC and is required for induction of AR. Preliminary data also demonstrate a moderate cell cycle block and a more profound induction of senescence, which is dependent on this pathway. This project will interrogate the role of this pathway in vitamin D signaling in the prostate stem cell in more detail. We will evaluate the mechanism of regulation by vitamin D and how this pathway intersects with AR signaling, we will determine the signaling pathway leading to senescence in response to vitamin D both in vitro and in vivo, and we will test the ability of vitamin D to block prostate tumor progression in a genetic model of prostate cancer that exhibits progression through prostatic intraepithelial neoplasia in a p27-dependent manner. Overall these studies will impact our understanding of the effects of vitamin D signaling on prostate stem cell growth arrest, differentiation and senescence and the functional roles of vitamin D in the prevention of prostate tumor progression.

Public Health Relevance

Prostate cancer is a significant health problem in the US which is a candidate disease for chemoprevention strategies. This project will dissect the underlying mechanisms of vitamin D-induced changes on the prostate stem cell, a viable target for chemoprevention strategies. This project will further our efforts to develop rationale chemoprevention strategies for prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OTC-B (03))
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Riscuta, Gabriela
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University of Colorado Denver
Schools of Medicine
United States
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Nieto, Cera M; Rider, Leah C; Cramer, Scott D (2014) Influence of stromal-epithelial interactions on androgen action. Endocr Relat Cancer 21:T147-60
Maund, Sophia L; Shi, Lihong; Cramer, Scott D (2013) A role for interleukin-1 alpha in the 1,25 dihydroxyvitamin D3 response in mammary epithelial cells. PLoS One 8:e81367
Maund, Sophia L; Barclay, Wendy W; Hover, Laura D et al. (2011) Interleukin-1? mediates the antiproliferative effects of 1,25-dihydroxyvitamin D3 in prostate progenitor/stem cells. Cancer Res 71:5276-86
Maund, Sophia L; Cramer, Scott D (2011) The tissue-specific stem cell as a target for chemoprevention. Stem Cell Rev 7:307-14