Journal of the National Cancer Institute Advance Access originally published online on February 24, 2009
JNCI Journal of the National Cancer Institute 2009 101(5):306-320; doi:10.1093/jnci/djn512
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© The Author 2009. Published by Oxford University Press.
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Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer
Affiliations of authors: Department of Cancer Biology (DGM), Department of Hematopathology (TJM), Department of Biostatistics and Applied Math (SW, XW, K-AD, PFT), Department of Systems Biology (DT), Department of Thoracic/Head & Neck Medical Oncology (SML), Department of Urology (LLP, CAP, CGW), Department of Veterinary Medicine and Surgery (CS), Department of Pathology (PT), and Department of Genitourinary Medical Oncology (JK, CJL, EE), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Department of Pathology, University of Washington, Seattle, WA (FV-L); Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX (RT)
Correspondence to: Jeri Kim, MD, Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 1374, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: jekim{at}mdanderson.org).
Background: Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation.
Methods: Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 µg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided.
Results: The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051).
Conclusions: We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type– and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications.
| CONTEXT AND CAVEATS Prior knowledge Selenium and vitamin E have been associated with reduced incidence of prostate cancer in secondary analyses of two randomized, controlled phase III trials. Study design In this randomized, double-blind phase IIA chemoprevention trial, 39 men with prostate cancer were treated with 200 µg of selenium, 400 IU of vitamin E, both, or placebo for 3 to 6 weeks before surgery. The gene expression profile of each cell type and of each treatment group was determined. Contribution This study provided a proof-of-principle that prostate biopsy specimens can serve as a source of tissue for molecular interrogation. Differential gene expression related to selenium and/or vitamin E treatments was identified that was cell type specific and tissue zone specific and that may have clinical implications. Implications This preoperative model can be used to investigate differential gene expression associated with other treatments for prostate cancer. Limitations The study period was only 3 to 6 weeks long and contained only 39 patients. The expression of biomarkers that are modulated after a short intervention may not correlate with a clinical endpoint in large clinical trials. Sampling errors caused by the presence of multifocal tumors and by the diverse nature of the tumors can lead to errors in identification of biomarkers and false-negative findings. A large chemoprevention trial of selenium and vitamin E showed no evidence of a preventive effect, and so any supplement-induced changes noted in gene expression are not likely to predict for prevention efficacy. From the Editors
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Manuscript received April 30, 2008; revised December 18, 2008; accepted December 22, 2008.
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J Natl Cancer Inst 2009 101: 281.
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