A functional polymorphism in the promoter region ofGSTM1implies a complex role forGSTM1in breast cancer

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Abstract
Although a number of studies have been conducted to address the relation between a gene deletion polymorphism of glutathione S-transferase M1 (GSTM1) and breast cancer, no definite conclusion has been reached and no clear risk pattern has yet to emerge for GSTM1. We first conducted case-control studies that included 1920 subjects using a genotyping method allowing the definition of GSTM1-null (−/−), homozygous wild-type (+/+), and heterozygous (+/−) genotypes. The results show that GSTM1−/− confers an increased risk for breast cancer development compared with that in GSTM1-present individuals (+/+ and +/−), which was subsequently confirmed by a meta-analysis of all of the 41 relevant studies (odds ratio: 1.10, PGSTM1+/+ is also a risk genotype compared with GSTM1+/−. Furthermore, we identified a functional polymorphism in the GSTM1 promoter region associated with breast cancer. The variant allele modifies DNA binding to the AP-2α transcription factor, resulting in reduced promoter activity and mRNA expression. However, this low-activity allele is associated with reduced breast cancer risk. It seems that ∼60–70% expression from one allele of GSTM1 could suffice for protection against breast cancer; null activity and overactivity of GSTM1 are both disadvantageous. These results indicate a U-shaped association of GSTM1 with breast cancer, which challenges the linear gene-dosage effect of GSTM1 that was previously proposed. We recommend that a more complicated role for GSTM1 should be considered in breast cancer risk prediction.—Yu, K.D., Di, G.-H., Fan, L., Wu, J., Hu, Z., Shen, Z.-Z., Huang, W., Shao, Z.-M. A functional polymorphism in the promoter region of GSTM1 implies a complex role for GSTM1 in breast cancer.
Funding Information
  • National Basic Research Program of China (2006CB910501)
  • National Natural Science Foundation of China (30371580, 30572109)
  • Science and Technology Commission of Shanghai Municipality (06DJ14004, 06DZ19504)