Impact of hyperhomocysteinemia on breast cancer initiation and progression: epigenetic perspective.
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.
Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Panjagutta, Hyderabad, 500082, Andhra Pradesh, India.
Shaik Mohammad
SM
Naushad
Cheruku Apoorva
CA
Reddy
Konda
K
Kumaraswami
Shree
S
Divyya
Srigiridhar
S
Kotamraju
Suryanarayana Raju
SR
Gottumukkala
Raghunadha Rao
RR
Digumarti
Vijay Kumar
VK
Kutala
D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014805:Vitamin B 12 / Q000494:pharmacology
C090121:BNIP3 protein, human; D019313:BRCA1 Protein; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; C112305:TUBGCP2 protein, human; D025521:Tumor Suppressor Proteins; D006710:Homocysteine; D014805:Vitamin B 12