Are dietary factors involved in the association of CDH4 methylation and breast cancer risk?

Abstract

DNA methylation is one of the most important epigenetic modifications in breast cancer (BC) development, and long-term dietary habits have been shown to alter DNA methylation. Cadherin-4 (CDH4, a member of the cadherin family) encodes Ca2+-dependent cell-cell adhesion glycoproteins. We conducted a case-control study (380 newly-diagnosed breast cancers and 439 cancer-free controls) to explore the relationship of CDH4 methylation in peripheral blood leukocyte DNA (PBL), as well as its combined and interactive effects with dietary factors and lifestyle on BC risk. A case-only study (335 newly-diagnosed breast cancers) was conducted to analyze the association between CDH4 methylation in breast tissue DNA and dietary factors. CDH4 methylation were detected using quantitative methylation specific PCR (qMSP). Unconditional logistic regressions were used to analyze the association of CDH4 methylation in PBL DNA and BC risk. Cross-over analysis and unconditional logistic regression were used to calculate the combined and interactive effects between CDH4 methylation in PBL DNA and dietary factors in BC. CDH4 hypermethylation was significantly associated with increased BC risk in PBL DNA (ORadjusted (ORadj)= 2.70, 95% confidence interval (CI)= 1.90-3.83, P<0.001). CDH4 hypermethylation also showed significant combined effects with the consumption of <500 g/week vegetables (ORadj=4.33, 95% CI=2.63-7.10), ≤3 times/week allium vegetables (ORadj=7.00, 95% CI=4.17-11.77), <3 times/week fish (ORadj=7.92, 95% CI=3.79-16.53), <3 times/week milk (ORadj=6.30, 95% CI=3.41-11.66), >3 times/week overnight food (ORadj=4.63, 95% CI=2.69-7.99), ≥250 g/week pork (ORadj=5.59, 95% CI=2.94-10.62), and <1 time/month physical activity (ORadj=4.72, 95% CI=2.87-7.76). Moreover, consuming milk ≥ 1 times/month was significantly related with decreased risk of CDH4 methylation (OR=0.61, 95% CI=0.38-0.99) in breast tissue. Our findings may provide direct guidance on the dietary intake for specific methylated carriers to decrease their risk for developing BC.