Impact of Hyperhomocysteinemia on Breast Cancer Initiation and Progression: Epigenetic Perspective

Abstract

Our recent study showing association of hyperhomocysteinemia and hypomethioninemia in breast cancer and other studies indicating association of hyperhomocysteinemia with metastasis and development of drug resistance in breast cancer cells treated with homocysteine lead us to hypothesize that homocysteine might modulate the expression of certain tumor suppressors, i.e., RASSF1, RARβ1, CNND1, BRCA1, and p21, and might influence prognostic markers such as BNIP3 by inducing epigenetic alteration. To demonstrate this hypothesis, we have treated MCF-7 and MDA-MB-231 cells with different doses of homocysteine and observed dose-dependent inhibition of BRCA1 and RASSF1, respectively. In breast cancer tissues, we observed the following expression pattern: BNIP3 > BRCA1 > RARβ1 > CCND1 > p21 > RASSF1. Hyperhomocysteinemia was positively associated with BRAC1 hypermethylation both in breast cancer tissue and corresponding peripheral blood. Peripheral blood CpG island methylation of BRCA1 in all types of breast cancer and methylation of RASSF1 in ER/PR-negative breast cancers showed positive correlation with total plasma homocysteine. The methylation of RASSF1 and BRCA1 was associated with breast cancer initiation as well as progression, while BRCA1 methylation was associated with DNA damage. Vitamin B12 showed inverse association with the methylation at both the loci. RFC1 G80A and cSHMT C1420T variants showed positive association with methylation at both the loci. Genetic variants influencing remethylation step were associated positively with BRCA1 methylation and inversely with RASSF1 methylation. GCPII C1561T variant showed inverse association with BRCA1 methylation. We found good correlation of BRAC1 (r = 0.90) and RASSF1 (0.92) methylation pattern between the breast cancer tissue and the corresponding peripheral blood. To conclude, elevated homocysteine influences methionine dependency phenotype of breast cancer cells and is associated with breast cancer progression by epigenetic modulation of RASSF1 and BRCA1.

Turkish propolis supresses MCF-7 cell death induced by homocysteine

“…Apart from that, Hcy-induced DNA methylation patterns [11,34] might be another possible mechanism to explain distinct results of propolis treatment in the present study. The study of Naushad et al [34] has clearly revealed that hyperhomocysteinemia closely linked to epigenetic modification of DNA in MCF-7 cells line.…”

“…The study of Naushad et al [34] has clearly revealed that hyperhomocysteinemia closely linked to epigenetic modification of DNA in MCF-7 cells line. Therefore, it could be suggested that alterations of DNA methylation might evolve or interrupt biological activities of propolis.…”

“…In control group, cells were treated with just complete media. In Hcy group, cells were exposed to 50 mM Hcy [34] in complete media for 24 h. In cotreatment group, cells were incubated with 50 mM Hcy and 50 mg/ml propolis [35] in complete media for 24 h.…”

Gene expression profile comparison between colorectal cancer and adjacent normal tissues

“…CCND1 and MET are the receptors for the hepatocyte growth factor (HGF); the activation of HGF results in the phosphorylation of two MET-adjacent tyrosine residues, which in turn activates multiple signaling pathways, thereby promoting cell division, angiogenesis, tumor cell invasion and metastasis (41,42). CCND1 is a key factor in the regulation of the cell cycle, and its overexpression shortens the G1/S phase, such that cells produce less growth-dependent cytokines, which in turn affects tumor occurrence, development and prognosis (43).…”

Case of Thrombosis of Rare Localization in a Cancer Patient with Combined form of Thrombophilia

“…An increased level of homocysteine leads to an increase in the level of TF in the blood plasma-A key protein of the internal coagulation cascade, which is especially important in combination with the oncological process, as TF is one of the main procoagulant factors of tumor tissue. Homocysteine inhibits natural anticoagulant mechanisms, preventing the binding of antithrombin III to heparan sulfate, which is part of the endothelium, by blocking the interaction of membrane protein of thrombomodulin with thrombin, which is necessary for the activation of protein C [18,19].…”