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

Ke-Da Yu^*,1, Gen-Hong Di^*,1, Lei Fan^*,1, Jiong Wu^*, Zhen Hu^*, Zhen-Zhou Shen^*, Wei Huang and Zhi-Ming Shao^*,2

^* Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai, China; and

Chinese National Human Genome Center at Shanghai, Shanghai, China

² Correspondence: Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Rd., Shanghai, 200032, China. E-mail: zhimingshao{at}yahoo.com

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-2 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.

Key Words: risk pattern • AP-2 • meta-analysis • functional verification

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