Breast cancer is associated with methylation and expression of the a disintegrin and metalloproteinase domain�33 (ADAM33) gene affected by endocrine‑disrupting chemicals

Abstract

A disintegrin and metalloproteinase domain 33 (ADAM33) gene is a transmembrane glycoprotein that mediates changes in cell adhesion and plays an important role in cancer progression. Since bisphenol A (BPA) and phthalates are epigenetically toxic, the purpose of this study was to examine whether BPA and phthalate metabolites, including monoethyl phthalate (MEP), mono‑n‑butyl phthalate (MBP), mono‑isobutyl phthalate (MIBP), mono(2‑ethylhexyl) phthalate (MEHP), mono(2‑ethyl‑5‑hydroxyhexyl) phthalate (MEHHP), mono(2‑ethyl‑5‑carboxypentyl) phthalate (MECPP), and mono(2‑ethyl‑5‑oxohexyl) phthalate (MEOHP), have an epigenetic impact on ADAM33 and the incidence of breast cancer. CpG islands of breast cancer microarray datasets obtained from the Gene Expression Omnibus (GEO) were used to assess the ADAM33 methylation profile. We designed a case‑control study including 44 cases and 22 age‑matched controls to detect the methylation status of intron 1 in ADAM33 from peripheral blood mononuclear cells (PBMCs) in blood, using BSP, nested PCR, and bisulfite sequencing, and measured the in vivo gene expression of ADAM33 and the urinary concentrations of endocrine‑disrupting chemicals (EDCs), using real‑time PCR, high‑performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC‑MS). Only one dataset, GSE32393, reached significance (P=0.016). ADAM33 expression and methylation frequencies at CpG site 3 in intron 1 were higher in the control group. We found a positive association between intron 1 methylation level and ADAM33 expression as well as urinary concentrations of MEHHP, MECPP, MEOHP and Σ4MEHP (the sum of MEHP, MECPP, MEHHP, and MEOHP) in the cases. This study suggests that metabolites of phthalate such as MEHHP, MECPP, MEOHP and Σ4MEHP may increase the intron 1 methylation level to elevate ADAM33 gene expression and have a protective effect on reducing the risk of breast cancer.

Association between recurrent breast cancer and phthalate exposure modified by hormone receptors and body mass index

“…Compared to nonusers, the concentration of MiBP is higher in users of perfume 35 , 38 and MEOHP is higher in bottled water 38 . Our previous study found that MEHHP, MECPP, MEOHP, and Σ 4 DEHP were positively associated with increased intron 1 methylation level and gene expression in ADAM33 gene and the phenomenon may be related to decreased breast cancer risk 39 . Two studies and a multiethnic cohort study in whites observed an non-significant negative association between MEOHP and breast cancer 13 , 14 , 40 ; a prospective study and an Alaska study showed that MEOHP were not associated with breast cancer 12 , 15 .…”

New insight into the role of the ADAM protease family in breast carcinoma progression

“…Conversely, we discovered a potential association between increased urinary concentration of BPA and BC. Furthermore, MEP and MBP, both phthalate metabolites were negatively correlated with ADAM33 expression [ 106 ].…”

The adverse role of endocrine disrupting chemicals in the reproductive system

“…What’s interesting is that the co-exposure can produce antagonistic effect. Moreover, other authors found that PAEs metabolites could upregulate the expression of disintegrin and metalloproteinase domain 33 (ADAM33), which plays a significant role in reducing BC risk ( 215 ).…”