title: Molecular Subtype-Specific Expression of MicroRNA-29c in Breast Cancer Is Associated with CpG Dinucleotide Methylation of the Promoter.
abstract: Basal-like breast cancer is a molecularly distinct subtype of breast cancer that is highly aggressive and has a poor prognosis. MicroRNA-29c (miR-29c) has been shown to be significantly down-regulated in basal-like breast tumors and to be involved in cell invasion and sensitivity to chemotherapy. However, little is known about the genetic and regulatory factors contributing to the altered expression of miR-29c in basal-like breast cancer. We here report that epigenetic modifications at the miR-29c promoter, rather than copy number variation of the gene, may drive the lower expression of miR-29c in basal-like breast cancer. Bisulfite sequencing of CpG sites in the miR-29c promoter region showed higher methylation in basal-like breast cancer cell lines compared to luminal subtype cells with a significant inverse correlation between expression and methylation of miR-29c. Analysis of primary breast tumors using The Cancer Genome Atlas (TCGA) dataset confirmed significantly higher levels of methylation of the promoter in basal-like breast tumors compared to all other subtypes. Furthermore, inhibition of CpG methylation with 5-aza-CdR increases miR-29c expression in basal-like breast cancer cells. Flourescent In Situ Hybridization (FISH) revealed chromosomal abnormalities at miR-29c loci in breast cancer cell lines, but with no correlation between copy number variation and expression of miR-29c. Our data demonstrated that dysregulation of miR-29c in basal-like breast cancer cells may be in part driven by methylation at CpG sites. Epigenetic control of the miR-29c promoter by epigenetic modifiers may provide a potential therapeutic target to overcome the aggressive behavior of these cancers.
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Poli
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Chika
authors.initials: C
authors.lastname: Nwachukwu
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Babatunde
authors.initials: B
authors.lastname: Adedokun
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.affiliation: Center for Clinical Cancer Genetics and Global Health, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States of America.
authors.forename: Yoo-Jeong
authors.initials: YJ
authors.lastname: Han
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D035683:MicroRNAs