Urinary parabens and breast cancer risk: Modification and interaction by LINE-1/LUMA methylation in the Long Island Breast Cancer Study Project

Abstract

BACKGROUND AND AIM: Parabens, ubiquitous endocrine disrupting chemicals used in personal care products, may interact with DNA methylation status to impact breast cancer (BC) risk. We examined whether global DNA methylation modifies or interacts with paraben levels to impact BC risk and whether paraben levels are associated with tumor gene-specific promoter methylation in 12 BC-related genes. METHODS: Participants included 708 cases and 598 controls from the population-based Long Island Breast Cancer Study Project. Levels of methyl-/propyl-/butyl-parabens and parabens were measured in spot urine samples, creatinine-corrected, and dichotomized at the 80th percentiles. Global DNA methylation status (methylated vs. unmethylated) was measured in peripheral blood using LINE-1 and LUMA. Among 509 cases, the promoter methylation status of 12 BC-related genes was measured in tumor samples. For effect measure modification, we used logistic regression to estimate covariate-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the associations between paraben levels and BC stratified by LINE-1/LUMA methylation status. For additive interactions, we used logistic regression to estimate aORs and CIs for the joint associations between paraben levels and LINE-1/LUMA methylation status and BC. To examine outcome heterogeneity, we used multinomial logistic regression to estimate aORs and CIs for the associations between paraben levels and gene-specific promoter methylation status (unmethylated cases vs. controls; methylated cases vs. controls). RESULTS:Propylparaben levels 80th (vs. ≤80th) percentile were associated with a 50% increase in the odds of having a methylated APC promoter than being a control (aOR=1.50, 95%CI=1.02-2.20), but not with having an unmethylated APC promoter than being a control (aOR=0.94, 95%CI=0.63-1.42). LINE-1/LUMA did not modify the associations between parabens and BC and did not interact with parabens to increase BC risk. CONCLUSIONS:Exposure to parabens may increase the risk of BC with methylated promoter regions of APC, a tumor suppressor gene and regulator of the WNT signaling pathway. KEYWORDS: Breast cancer, parabens, endocrine disrupting chemicals, DNA methylation, gene promoter methylation