Urinary parabens and breast cancer risk: Modification by LINE-1 and LUMA global DNA methylation, and associations with breast cancer defined by tumor promoter methylation status.

Parabens are a group of alkyl esters of p-hydroxybenzoic acid added to consumer products to prevent the growth of harmful bacteria and molds. Parabens are hypothesized to increase the risk of breast cancer (BC); however, no study has examined the interactions between parabens, global DNA methylation (DNAm), and BC risk. We examined the modifying effects of DNAm on the associations between parabens and BC, and whether parabens were associated with BC defined by tumor promoter methylation status. Participants included 708 cases and 598 controls from the Long Island Breast Cancer Study Project. Methylparaben (MPB), propylparaben, and butylparaben levels were measured in spot urine samples. Global DNAm was measured by analysis of long interspersed elementes-1 (LINE-1) and the luminometric methylation assay (LUMA). The promoter methylation status of 13 genes was measured in tumor samples from 509 cases. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between parabens and BC stratified by LINE-1/LUMA, and between parabens and gene-specific promoter methylation-defined BC. Outcome heterogeneity was evaluated using ratios of ORs (RORs). We assessed the joint effects of the multiple parabens using quantile g-computation. The highest versus lowest tertile of MPB and a one-quantile increase in all parabens were associated with ORs of 1.46 (95% CI = 0.96-2.23) and 1.32 (95% CI = 1.02-1.71), respectively, among women with hypomethylated LINE-1. A one-ln unit increase in MPB was associated with a 25% increase in the odds of hypomethylated (vs. hypermethylated) CCND2 promoter-defined BC (ROR = 1.25, 95% CI = 1.06-1.48), and a one-quantile increase in all parabens was associated with a 55% increase in the odds of hypomethylated (vs. hypermethylated) CCND2 promoter-defined BC (ROR = 1.55, 95% CI = 1.04-2.32). Exposure to parabens may increase the risk of BC among women with hypomethylated global DNAm and may increase the risk of tumors with gene-specific hypomethylated promoter regions.