A functional polymorphism in the promoter region of GSTM1 implies a complex role for GSTM1 in breast cancer

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, P<0.001). Unexpectedly, we found that GSTM1 –/– 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. FASEBJ. 23, 2274–2287 (2009)