Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53.

Abstract

We hypothesized that NRH:quinone oxidoreductase 2 (NQO2) is a candidate susceptibility gene for breast cancer because of its known enzymatic activity on estrogen-derived quinones and its ability to stabilize p53. We performed case-control studies to investigate the contributions of genetic variants/haplotypes of the NQO2 gene to breast cancer risk. In the first hospital-based study (n = 1604), we observed significant associations between the incidence of breast cancer and a 29 bp-insertion/deletion polymorphism (29 bp-I/D) and the rs2071002 (+237A>C) polymorphism, both of which are located within the NQO2 promoter region. Decreased risk was associated with the D-allele of 29 bp-I/D [odds ratio (OR), 0.76; P = 0.0027] and the +237C-allele of rs2071002 (OR, 0.80; P = 0.0031). Specifically, the susceptibility variants within NQO2 were notably associated with breast carcinomas with wild-type p53 (the most significant P-value: 3.3 x 10(-6)). The associations were successfully replicated in an independent population set (familial/early-onset breast cancer cases and community-based controls, n = 1442). The combined P-values of the two studies (n = 3046) are 3.8 x 10(-7) for 29 bp-I/D and 2.3 x 10(-6) for rs2071002. Furthermore, we revealed potential mechanisms of pathogenesis of the two susceptibility polymorphisms. Previous work has demonstrated that the risk-allele I-29 of 29 bp-I/D introduces transcriptional-repressor Sp3 binding sites. Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele, +237A-allele of rs2071002, abolishes a transcriptional-activator Sp1 binding site. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Taken together, the data presented here strongly suggest that NQO2 is a susceptibility gene for breast carcinogenesis.

• Authors: Ke-Da Yu, Gen-Hong Di, Wen-Tao Yuan, Lei Fan, Jiong Wu, Zhen Hu, Zhen-Zhou Shen, Ying Zheng, Wei Huang, Zhi-Ming Shao
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 18 Issue 13 Pg. 2502-17 (Jul 01 2009) ISSN: 1460-2083 [Electronic] England
• PMID: 19351655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Protein p53
• NRH - quinone oxidoreductase2
• Quinone Reductases

Topics

• Adult
• Asian People (genetics)
• Base Sequence
• Breast Neoplasms (enzymology, genetics, pathology)
• Case-Control Studies
• Cell Line, Tumor
• China
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Middle Aged
• Molecular Sequence Data
• Mutation
• Polymorphism, Genetic
• Promoter Regions, Genetic
• Quinone Reductases (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)