Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPAR-γ) gene and risk of prostate cancer among men in a large cancer prevention study
Introduction
The peroxisome proliferator-activated receptor (PPAR) is a nuclear hormone receptor that belongs to the family of ligand-activated transcription factors [1]. Three distinct isoforms, PPAR-α, PPAR-β, and PPAR-γ, have been identified, each with a specific pattern of expression. These receptors are activated by dietary factors such as fatty acids and their metabolites [2], and may also be involved in controlling genes relevant to the process of carcinogenesis [3]. PPAR-γ specifically plays an important role in adipocyte differentiation and is involved in the uptake, metabolism and storage of fatty acids [2]. Physiologically, activation of PPAR-γ decreases the production of glucose in the liver, increases muscle utilization of glucose, and increases the efflux of cholesterol that is mediated by macrophages [2], and controls cell proliferation and differentiation [4]. PPAR-γ has been implicated to play a role in the progression of prostate cancer. Both normal and malignant prostatic tissues have been shown to express PPAR-γ [5], [6], [7]. Heterozygous deletions in the 3p25 region containing PPAR-γ have been found in up to 30% of patients with prostate cancer [4]. Further, data have indicated that ligand activation of PPAR-γ inhibits growth, induces apoptosis, and modulates prostate specific antigen (PSA) levels in prostate cancer cell lines, and stabilizes PSA levels in prostate cancer patients [8].
Pro12Ala is a missense mutation in the PPAR-γ2 specific exon whereby proline (Pro) has been substituted for alanine (Ala) in codon 12. The frequency of the PPAR-γ2 Ala allele in Caucasian populations, including Finnish populations, has been shown to range from 0.11 to 0.22 [9], [10], [11], [12]. In humans, the Ala12 allele has been associated with physiologic changes such as weight gain over time and alterations in body mass index (BMI) [7], [11], [13], increased insulin sensitivity [10], [14], and altered lipid profiles [15], thus possibly implicating this polymorphism in cardiovascular disease risk. These findings, however, are not consistent across the literature.
The fact that PPAR-γ is expressed in malignant prostatic tissue and that its ligands have been shown to inhibit prostate cancer cell growth and stabilize serum PSA levels over time in patients [8] led us to examine the Pro12Ala polymorphism and its association with prostate cancer. In this investigation, we assess the relationship of the Pro12Ala germline polymorphism in the PPAR-γ2 gene with prostate cancer risk in participants of the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a large, randomized intervention trial conducted in Finland. As a secondary analysis, we also examined the association between this polymorphism and the clinical aggressiveness of prostate cancer, as measured by stage and grade of disease.
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Study subjects
This study was conducted in a cohort of the 29, 133 white male smokers who participated in the ATBC Study conducted in Finland (1985–1993). The ATBC Study was a randomized, placebo-controlled primary prevention trial that assessed whether supplementation with α-tocopherol (50 mg/day) or β-carotene (20 mg/day), or both, reduced the incidence of lung and other cancers among men that smoked at least five cigarettes per day [16]. This study received institutional review board approval from both the
Results
Incident prostate cancer cases and their matched controls did not differ statistically by various demographic, dietary or medical characteristics (Table 1). For the prostate cancer cases, the mean age at prostate cancer diagnosis was 66.1±5.4 years, with an average time to diagnosis of 5.5±2.1 year from baseline.
We observed no significant differences in the distribution of the PPAR-γ genotype among the cases and controls (Table 2). The distribution among our control population is similar to
Discussion
In the present investigation, we assessed the association between the Pro12Ala polymorphism in the PPAR-γ2 gene and prostate cancer among participants in the ATBC Cancer Prevention Study. We did not observe a significant association between the variant genotype and risk of prostate cancer overall or between the genotype and disease stage or grade.
Epithelial tissues of several human cancers have been found to express the PPAR-γ subtype including colon cancer, breast cancer, and prostate cancer
Acknowledgements
The authors would like to thank Douglas Weed (Director), Stephen Hursting (Deputy Director) and La Cries Renee Kidd (Fellow) of the Cancer Prevention Fellowship Program; Ramakrishna Modali, Kristin Taylor and Mike Seddan at BioServe Biotechnologies in Gaithersburg, MD; and Mike Barrett, Kirk Snyder, and Carly Tan at Information Management Services, Inc. for data management and support. This study is supported by the Public Health Service contract N01 CN 45165 and 45035 from the National Cancer
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Dina Paltoo is supported by the Cancer Prevention Fellowship Program, Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA, http://www.cancer.gov/prevention/pob/