Early-stage prostate cancer: Biological features and modification by dietary intervention

Yan Li, Purdue University

Abstract

Prostate cancer is an important public health problem and its prevention by dietary intervention may reduce the morbidity and mortality associated with this disease. Low vitamin D status (i.e., low serum 25-hydroxytvitamin D) has been correlated with increased risk of prostate cancer in several population studies. The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) regulates transcription of vitamin D target genes by interacting with the vitamin D receptor (VDR), a ligand activated transcription factor. High-grade prostatic intraepithelial neoplasia (HGPIN) is recognized as the precursor of prostate cancer and represents a target of chemoprevention. In order to advance our knowledge of the molecular features of HGPIN, to examine the importance of VDR in vitamin D-mediated prostate cancer prevention, and to develop a dietary regimen that can enhance vitamin D anti-prostate cancer effect in vivo, we conducted three studies using the TgAPT 121 mouse model of early-stage prostate cancer. In the first study, we used DNA microarray to characterize the gene expression profile of TgAPT 121 mouse prostate which harbored extensive mouse PIN lesions resembling human HGPIN. Enrichment analysis of the 3743 differentially expressed genes revealed alterations of cellular processes related to DNA damage response, apoptosis, amino acid metabolism, and various cell signaling pathways. Activation of p53 signaling was suggested by both pathway enrichment analysis and gene network analysis, and p53 stabilization was demonstrated by immunohistochemical staining. Apoptosis activation was confirmed by TUNEL staining. These findings suggest that important cancer suppressive mechanisms are activated in PIN-stage prostate, which may function to suppress the malignant transformation of these precursor lesions. In the second study, we deleted the VDR gene from the prostate of TgAPT121 mice and examined its impact on cancer development. We found that VDR is significantly upregulated in PIN-stage TgAPT 121 mouse prostate, which may render these mice sensitive to VDR deletion. Indeed, VDR deletion from either the prostate epithelial cells alone or from the entire prostate resulted in enhanced prostate cancer development in these mice. These results provide direct in vivo evidence that vitamin D signaling through VDR is crucial for vitamin D-mediated prostate cancer prevention. In the third study, we examined whether dietary soy isoflavones at levels relevant to human intake could modulate 1,25(OH)2D metabolism and synergize with high vitamin D intake to influence bone and prostate endpoints in vivo. We found that at the level used in our study, soy isoflavones did not influence 1,25(OH)2D metabolism in the vitamin D endocrine system. However, they exerted a vitamin D-independent beneficial effect on bone, and suppressed prostate cancer development in TgAPT121 mice. More importantly, they synergized with high vitamin D intake to exert a stronger protective effect against prostate cancer. These results suggest that men may benefit from dietary patterns of high vitamin D and soy isoflavone intake for protection of prostate and bone health.

Degree

Ph.D.

Advisors

Fleet, Purdue University.

Subject Area

Nutrition

COinS