title: A functional variant in NKX3.1 associated with prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
abstract: NKX3.1 is an androgen-regulated prostate tumor suppressor protein. We previously found that antioxidant administration (N-acetylcysteine) in the Nkx3.1 knockout mouse model promoted prostate epithelial proliferation, suggesting that NKX3.1 activity modifies the effect of antioxidant administration on prostate carcinogenesis. Interestingly, administration of the antioxidant vitamin E significantly increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), suggesting that our animal experiments may be relevant to humans. To determine whether NKX3.1 played a role in increased human prostate cancer risk associated with antioxidant administration in SELECT, we investigated the joint risk of antioxidant administration and NKX3.1 genotypes previously found to be associated with decreased NKX3.1 mRNA expression (rs11781886) or DNA-binding activity in vitro (rs2228013) in the SELECT biomarker case-cohort substudy (1,866 cases; 3,135 non-cases). Multivariable COX regression models were developed to determine the joint association of NKX3.1 genotypes with administration of vitamin E, selenium, or the combination, compared with placebo. The CC genotype at rs11781886 combined with selenium administration was associated with increased overall prostate cancer risk [HR, 1.676; 95% confidence interval (CI), 1.011-2.777; P = 0.045] and low-grade prostate cancer risk (HR, 1.811; 95% CI, 1.016-3.228; P = 0.0441). Similarly, the rs11781886 minor allele (CC+CT) combined with vitamin E administration was significantly associated with increased prostate cancer risk (HR, 1.450; 95% CI, 1.117-1.882; P = 0.0052). Our results indicate that variation in NKX3.1 expression combined with selenium or vitamin E treatment modifies the risk of prostate cancer. Genetic background may modulate the effects of antioxidant supplementation thought to act as chemoprevention agents.
authors.affiliation: Departments of Pathology, Microbiology and Immunology.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Martinez
authors.affiliation: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington;
authors.forename: Amy K
authors.initials: AK
authors.lastname: Darke
authors.affiliation: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington;
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Tangen
authors.affiliation: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington;
authors.forename: Phyllis J
authors.initials: PJ
authors.lastname: Goodman
authors.affiliation: Surgical Urology, Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Jay H
authors.initials: JH
authors.lastname: Fowke
authors.affiliation: Cleveland Clinic Foundation, Cleveland, Ohio; and.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: Departments of Pathology, Microbiology and Immunology, Cancer Biology, and Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois sarki.abdulkadir@northwestern.edu.
authors.forename: Sarki A
authors.initials: SA
authors.lastname: Abdulkadir
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000627:therapeutic use*; D016022:Case-Control Studies; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D014810:Vitamin E / Q000627:therapeutic use*; D014815:Vitamins / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors; D014815:Vitamins; D014810:Vitamin E