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

• Published in: The FASEB journal Vol. 23; no. 7; pp. 2274 - 2287
• Main Authors: Yu, Ke-Da, Di, Gen-Hong, Fan, Lei, Wu, Jiong, Hu, Zhen, Shen, Zhen-Zhou, Huang, Wei, Shao, Zhi-Ming
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.07.2009
• Subjects: Asian Continental Ancestry Group - genetics; Breast Neoplasms - epidemiology; Breast Neoplasms - etiology; Breast Neoplasms - genetics; Case-Control Studies; Cell Line, Tumor; China - epidemiology; Female; Genotype; Glutathione Transferase - genetics; Humans; Polymorphism, Genetic - physiology; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Protein Binding - genetics; RNA, Messenger - analysis; Transcription Factor AP-2 - metabolism; China
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.08-124073

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.