Computational analysis of microRNA profiles and their target genes suggests significant involvement in breast cancer antiestrogen resistance.

School of Informatics, Indiana University, Bloomington, IN 47405, USA.
Bioinformatics (Impact Factor: 5.47). 01/2009; 25(4):430-4. DOI: 10.1093/bioinformatics/btn646
Source: PubMed

ABSTRACT MOTIVATION: Recent evidence shows significant involvement of microRNAs (miRNAs) in the initiation and progression of numerous cancers; however, the role of these in tumor drug resistance remains unknown. RESULTS: By comparing global miRNA and mRNA expression patterns, we examined the role of miRNAs in resistance to the 'pure antiestrogen' fulvestrant, using fulvestrant-resistant MCF7-FR cells and their drug-sensitive parental estrogen receptor (ER)-positive MCF7 cells. We identified 14 miRNAs downregulated in MCF7-FR cells and then used both TargetScan and PITA to predict potential target genes. We found a negative correlation between expression of these miRNAs and their predicted target mRNA transcripts. In genes regulated by multiple miRNAs or having multiple miRNA-targeting sites, an even stronger negative correlation was found. Pathway analyses predicted these miRNAs to regulate specific cancer-associated signal cascades. These results suggest a significant role for miRNA-regulated gene expression in the onset of breast cancer antiestrogen resistance, and an improved understanding of this phenomenon could lead to better therapies for this often fatal condition.

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    ABSTRACT: MicroRNA (miRNA) expression has been found to be deregulated in human cancer, contributing, in part, to the interest of the research community in using miRNAs as alternative therapeutic targets. Although miRNAs could be potential targets, identifying which miRNAs to target for a particular type of cancer has been difficult due to the limited knowledge on their regulatory roles in cancer. We address this challenge by integrating miRNA-target prediction, metabolic modeling and context-specific gene expression data to predict therapeutic miRNAs that could reduce the growth of cancer. Results: We developed a novel approach to simulate a condition-specific metabolic system for human hepatocellular carcinoma wherein overexpression of each miRNA was simulated to predict their ability to reduce cancer cell growth. Our approach achieved more than 80 percent accuracy in predicting the miRNAs that could suppress metastasis and progression of liver cancer based on various experimental evidences in the literature. This condition-specific metabolic system provides a framework to explore the mechanisms by which miRNAs modulate metabolic functions to affect cancer growth. To the best of our knowledge, this is the first computational approach implemented to predict therapeutic miRNAs for human cancer based upon their functional role in cancer metabolism. Analyzing the metabolic functions altered by the miRNAs identified metabolic genes essential for cell growth and proliferation that are targeted by the miRNAs. Availability and Implementation: see supplementary protocols and
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs generated by a two-step complex process and are post transcriptional negative regulators of their target mRNAs. Dysregulation of many of these miRNAs has been associated with tumorigenesis in various cancers including breast cancer. Aberrantly high expression of specific miRNAs in breast cancer cells is demonstrated to be linked with inhibition of tumor suppressor genes and promote tumorigenesis. They are classified as oncogenic miRNAs. However, the tumor suppressor miRNAs are downregulated in breast cancer cells, since their major targets are oncogenic mRNAs. Understanding mechanism of action of specific miRNAs in breast cancer cells can be utilized to develop newer anti-cancer therapies. Recently, newer techniques are also developed to detect abundance of specific miRNA in the blood plasma samples and can be used in early diagnosis or prognosis in breast cancer. In this review article, we have discussed several miRNAs dysregulated in breast cancer and their therapeutic potential.
    World journal of clinical oncology. 05/2014; 5(2):48-60.

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