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.

The Impact of Vitamin D and Its Dietary Supplementation in Breast Cancer Prevention: An Integrative Review

“…Various authors have highlighted the importance of methylation in the relationship between vitamin D and BC, as the methylation levels of some genes, such as RXR, or hypermethylation of the VDR promoter, could affect vitamin D levels and the risk of developing BC [ 90 , 120 , 121 , 122 ]. Furthermore, epigenetics can also be related to factors such as diet [ 123 ]. Other epigenetic modifications may also be related to vitamin D levels and the risk of developing BC, such as histone methylation [ 50 , 124 ] and the regulation and expression of miRNAs [ 125 , 126 , 127 ].…”

Development of a Prognostic Model for HR-positive HER2-negative and Node-negative Breast Cancer: Integrating Clinical and Transcriptional Biomarkers

“…TBLR1/TBL1XR1 acts as an ER corepressor and inhibits ER-mediated transcriptional activation in breast cell lines, and nuclear TBLR1 overexpression increases migration and invasion of breast cancer cells [42]. CDH4 encodes Ca2+-dependent intercellular adhesion glycoproteins, and hypermethylation of CDH4 is an independent risk factor for the development of breast cancer [43]. GATA6 is elevated in breast cancer and its expression level positively correlates with metastasis, leading to reduced overall survival [44].…”

Expression and associated epigenetic mechanisms of the Ca2+-signaling genes in breast cancer subtypes and epithelial-to-mesenchymal transition

“…DSC3 and FAT promoter is methylated in breast cancer samples and cell lines, and the DNMTi 5-Aza-2-deoxycytidine (5-Aza) increases their expression (Oshiro et al 2005;Qi et al 2009;Wozniak et al 2007). Promoter methylation of CDH4 in peripheral blood leukocytes is associated with an increased risk of breast cancer, however, the role of DNA methylation in breast cancer tissue was not evaluated (N. Zhang et al 2021). DNA methylation of the promoter of CDH13 was positively associated with HER2 expression in tumor samples and with breast cancer risk (Fiegl et al 2006;Yang et al 2016).…”