Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer
Wee, E.J.H., Peters, K., Nair, S.S., Hulf, T., Stein, S., Wagner, S., Bailey, P., Lee, S.Y., Qu, W.J., Brewster, B., French, J.D., Dobrovic, A., Francis, G.D., Clark, S.J., & Brown, M.A. (2012) Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer. Oncogene, 31(38), pp. 4182-4195.
MicroRNAs (miRNAs) are small non-coding RNAs of 20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located 2 kb upstream of the 5′ stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.
Impact and interest:
Citation counts are sourced monthly from and citation databases.
These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.
Citations counts from theindexing service can be viewed at the linked Google Scholar™ search.
|Item Type:||Journal Article|
|Keywords:||breast cancer, DNA methylation, MicroRNA, miR-200b, prognosis, promoter, androgen receptor, epidermal growth factor receptor 2, estrogen receptor, microRNA 200b, progesterone receptor, adult, advanced cancer, aged, article, breast metastasis, cancer cell, controlled study, female, human, human cell, human tissue, in vitro study, lymph node metastasis, major clinical study, priority journal, promoter region, protein expression, regulatory sequence, Aged, 80 and over, Breast Neoplasms, Cell Line, Tumor, Chromosome Mapping, CpG Islands, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Middle Aged, Multigene Family, Neoplasm Metastasis, Promoter Regions, Genetic, Receptor, erbB-2, Receptors, Estrogen, Receptors, Progesterone, Reproducibility of Results, Transcription Initiation Site|
|Divisions:||Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright 2012 Macmillan Publishers Limited|
|Deposited On:||20 Oct 2015 22:29|
|Last Modified:||25 Feb 2016 03:36|
Repository Staff Only: item control page