Purpose Here we assessed associations between null mutations in glutathione-S-transferase (GST)and genes and the rs1695 polymorphism in (Ile105Val) and risk of breast cancer-specific (n=45) and all-cause (n=99) mortality in a multiethnic prospective cohort of 533 women diagnosed with stage I-IIIA breast cancer in 1995-1999 enrolled in the Health Eating Activity and Lifestyle (HEAL) Study. ER-negative tumors were more likely to be null (χ2=4.52; P=0.03) and African American women were more likely to be null (χ2=34.36; P<0.0001). Neither nor null mutations were associated with breast cancer-specific or all-cause mortality. In a model adjusted for body mass index race/ethnicity tumor stage and treatment received at diagnosis the variant Val allele of rs1695 was associated with increased risk of all-cause (HR=1.81 95 CI 1.16-2.82 P=0.008) but not breast cancer-specific mortality. The GSTT1 null mutation was associated with significantly higher levels of C-reactive protein. Conclusions GSTM1 and GSTT1 null genotypes had no effect on outcome; however the variant allele of rs1695 appears to confer increased risk for all-cause mortality in breast-cancer survivors. Given the limited sample size of most studies examining associations between GST polymorphisms with breast cancer survival and the lack of women undergoing more contemporary treatment protocols (treated prior to 1999) it may be helpful to re-examine this issue among larger samples of women diagnosed after the late 1990s who all received some form of chemotherapy or radiotherapy. genes respectively; and these 3 genes have been studied in association with genetic susceptibility to cancer (Strange & Fryer 1999; Spurdle et al. 2010). Homozygous deletion of the and genes (null genotype) are associated with a lack of enzyme function and increased vulnerability to cytogenetic damage (Seidegard et al. 1988). Individuals who have deletions in or may therefore be at increased cancer risk (Strange & Fryer 1999; Rebbeck 1997). The GST π (P1) polymorphism (rs1695; an A→G transition at position 313) results in an Ile→Val change at codon 105 (Ile105Val). The variant allele is associated with lower substrate-specific catalytic activity including towards the alkylating anticancer agent chlorambucil (Hayes & Strange 2000; Pandya et al. 2000; Srivastava et al. 1999). A limited number of studies with conflicting results have PIK-293 investigated the association between polymorphisms in genes and mortality in breast cancer patients. The majority of these studied patients diagnosed prior to 1999. Five of six studies have samples of women undergoing chemotherapy and/or radiotherapy and most examined only one gene (usually Val allele but no association with either or and risk of death (Yang et al. 2005). In two reports based on the same sample women with breast cancer with null mutations for and had reduced risk of death compared to women with alleles present (Ambrosone et al. 2001) and a reduction in mortality risk for women homozygous for the variant Val allele compared to those PIK-293 homozygous for the Ile allele (Sweeney et al. 2000; Yang et al. 2005). Finally 2 other small studies examined associations between one GST polymorphism among women treated with high dose chemotherapy one reported PIK-293 no association between survival and null; (Lizard-Nacol et al. 1999) another that the Val/Val polymorphism was non-significantly associated with worse PIK-293 overall survival (Bewick et al. 2008). Two studies (one in smokers and the other in patients with diabetes) reported an association between and null mutations and lower levels of the Rabbit Polyclonal to C1QC. inflammatory biomarker CRP (Hayek et al. 2006; Miller et al. 2003) itself associated with poor survival (Pierce et al. 2009a). We thus examined this association in the Health Eating Activity and Lifestyle (HEAL) study. We extend prior research by examining the association between three different GST isoenzymes (null mutations in and to Stage IIIA breast cancer between 1996-1999. In WA we recruited 202 women aged 40-64 years diagnosed PIK-293 with Stage 0-Stage IIIA breast cancer between 1997-1998. In CA we recruited 366 Black women aged 35-64 years with Stage 0-Stage IIIA breast cancer who had participated in the Los Angeles portion of the Women’s Contraceptive and Reproductive Experiences Study diagnosed with breast cancer between 1995-1998. Recruitment was restricted in WA and PIK-293 CA to women aged 35-64 at diagnosis because of competing studies and parent study design. The study was performed with the approval of the Institutional Review Boards of participating centers in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services. Written informed consent was obtained from each subject. 944 women completed in-person interviews approximately 30-months following their first interview; 726.