Naushad Shaik Mohammad, Reddy Cheruku Apoorva, Kumaraswami Konda, Divyya Shree, Kotamraju Srigiridhar, Gottumukkala Suryanarayana Raju, Digumarti Raghunadha Rao, Kutala Vijay Kumar
Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Panjagutta, Hyderabad, 500082, Andhra Pradesh, India.
Cell Biochem Biophys. 2014 Mar;68(2):397-406. doi: 10.1007/s12013-013-9720-7.
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.
我们最近的研究表明高同型半胱氨酸血症与乳腺癌中的低蛋氨酸血症相关，其他研究表明高同型半胱氨酸血症与用同型半胱氨酸处理的乳腺癌细胞的转移和耐药性发展相关，这使我们推测同型半胱氨酸可能调节某些肿瘤抑制因子的表达，即RASSF1、RARβ1、CCND1、BRCA1和p21，并可能通过诱导表观遗传改变影响诸如BNIP3等预后标志物。为了验证这一假设，我们用不同剂量的同型半胱氨酸处理MCF-7和MDA-MB-231细胞，分别观察到BRCA1和RASSF1的剂量依赖性抑制。在乳腺癌组织中，我们观察到以下表达模式：BNIP3>BRCA1>RARβ1>CCND1>p21>RASSF1。高同型半胱氨酸血症在乳腺癌组织和相应外周血中均与BRAC1高甲基化呈正相关。所有类型乳腺癌中BRCA1的外周血CpG岛甲基化以及雌激素受体/孕激素受体阴性乳腺癌中RASSF1的甲基化与血浆总同型半胱氨酸呈正相关。RASSF1和BRCA1的甲基化与乳腺癌的发生以及进展相关，而BRCA1甲基化与DNA损伤相关。维生素B12在两个位点的甲基化均呈负相关。RFC1 G80A和cSHMT C1420T变体在两个位点的甲基化均呈正相关。影响再甲基化步骤的基因变体与BRCA1甲基化呈正相关，与RASSF1甲基化呈负相关。GCPII C1561T变体与BRCA1甲基化呈负相关。我们发现乳腺癌组织和相应外周血之间BRAC1（r = 0.90）和RASSF1（0.92）甲基化模式具有良好的相关性。总之，同型半胱氨酸升高影响乳腺癌细胞的蛋氨酸依赖表型，并通过RASSF1和BRCA1的表观遗传调节与乳腺癌进展相关。
