Promoter Hypermethylation and Suppression of Glutathione Peroxidase 3 Are Associated with Inflammatory Breast Carcinogenesis

Abstract

Reactive oxygen species (ROS) play a crucial role in breast cancer initiation, promotion, and progression. Inhibition of antioxidant enzymes that remove ROS was found to accelerate cancer growth. Studies showed that inhibition of glutathione peroxidase-3 (GPX3) was associated with cancer progression. Although the role of GPX3 has been studied in different cancer types, its role in breast cancer and its epigenetic regulation have not yet been investigated. The aim of the present study was to investigate GPX3 expression and epigenetic regulation in carcinoma tissues of breast cancer patients' in comparison to normal breast tissues. Furthermore, we compared GPX3 level of expression and methylation status in aggressive phenotype inflammatory breast cancer (IBC) versus non-IBC invasive ductal carcinoma (IDC). We found that GPX3 mRNA and protein expression levels were downregulated in the carcinoma tissues of IBC compared to non-IBC. However, we did not detect significant correlation between GPX3 and patients' clinical-pathological prosperities. Promoter hypermethylation of GPX3 gene was detected in carcinoma tissues not normal breast tissues. In addition, IBC carcinoma tissues showed a significant increase in the promoter hypermethylation of GPX3 gene compared to non-IBC. Our results propose that downregulation of GPX3 in IBC may play a role in the disease progression.

Epigenetic regulation of Keap1-Nrf2 signaling

“…For example, the hypermethylation of CpG islands in the promoter region and expression silencing of pi class glutathione S-transferase (GSTPi) have been observed in prostate cancers [31]. NAD(P)H:quinone oxidoreductase 1 (NQO1), UDP-glucuronosyltransferases 1A1 (UGT1A1), glutathione peroxidase (GPX), and manganese superoxide dismutase (MnSOD) have also been reported to be regulated by promoter methylation [30, 36-38]. Regulation of Keap1 and Nrf2 expression by DNA methylation has been investigated in recent years and is discussed below and summarized in Table 1.…”

Inflammatory breast cancer: High incidence of GCC haplotypes (−1082A/G, −819T/C, and −592A/C) in the interleukin-10 gene promoter correlates with over-expression of interleukin-10 in patients’ carcinoma tissues

“…Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as a reference gene. 6 Experiments were conducted in duplicates and threshold cycle differences (ΔCt) were then averaged and results were normalized to endogenous control GAPDH expression fold to compensate PCR inter-variation and calculations have been done according to the 2−ΔΔCt formula.…”

Troglitazone inhibits the migration and invasion of PC‑3 human prostate cancer cells by upregulating E‑cadherin and glutathione peroxidase 3

“…It is well known that glutathione peroxidases are among the most important reactive oxygen species scavengers that protect cells from oxidative damage (36). Downregulation of GPx3 by hypermethylation has been revealed in numerous types of cancer (37)(38)(39)(40)(41)(42)(43)(44)(45), including prostate cancer (11,46,47). In prostate cancer, a negative correlation between GPx3 expression levels and poor clinical outcomes has been demonstrated (47,48).…”