title: Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients.
abstract: Breast cancer is fast emerging as the leading cancer amongst females, especially in younger age group in India; a large proportion of these tumors are often aggressive and ER and/or PR negative. Promoter methylation of genes involved in DNA repair and hormonal regulation may, in part, account for this behavior. To test this hypothesis methylation status of tumor suppressor genes TMS1, BRCA1, ERalpha and PRB was determined in invasive ductal carcinoma of breast and paired serum DNA. Of the 50 breast cancer patients investigated, 36/50 (72%) tumors and 32/50 (64%) paired sera showed methylation of at least one of these genes, while 17/50 (34%) tumors and 12/50 (24%) sera showed methylation of three genes. Methylation frequencies ranged from 24% for TMS1 to 63% for ERalpha. Significant association was observed between ERalpha and PRB methylation (p< or =0.001) and there was concordance between DNA methylation in tumor and serum for each gene. Immunohistochemical analysis showed no detectable expression of ERalpha, PRB and BRCA1 in 21/36 (58%), 20/36 (56%) and 23/36 (64%) tumors respectively; significant correlation was observed between promoter methylation and loss of protein expression confirming our hypothesis that promoter methylation is an important mechanism for transcriptional silencing of these genes in breast cancer in this population. This study also underscores the potential utility of DNA methylation based screening of serum (a surrogate for tumor DNA methylation) as a tool for detection of breast cancer.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
authors.forename: Sameer
authors.initials: S
authors.lastname: Mirza
authors.forename: Gayatri
authors.initials: G
authors.lastname: Sharma
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Prasad
authors.forename: Rajinder
authors.initials: R
authors.lastname: Parshad
authors.forename: Anurag
authors.initials: A
authors.lastname: Srivastava
authors.forename: Siddartha Dutta
authors.initials: SD
authors.lastname: Gupta
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D018270:Carcinoma, Ductal, Breast / Q000097:blood* / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011980:Receptors, Progesterone / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; C402202:PYCARD protein, human; D011980:Receptors, Progesterone