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: 4.98). 02/2009; 25(4):430-4. DOI: 10.1093/bioinformatics/btn646
Source: PubMed


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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Available from: Curt Balch, Mar 15, 2014
    • "TABLE III. MiRNAS Related to Chemotherapy Resistance in the Literature and Detected in Our Study miRNAs from the bibliography miRNA doxorubicin- deregulated by groups in our study * Validated Target Mechanism Drug Cancer Reference hsa-let-7 III (let-7-5p) V (let-7d-3p) ESR1, RAS, CASP3, HMGA2 Cellular response, EMT, hormone receptor status Doxorubicin; Doxorubicinþverapamil; fulvestrant, cisplatin breast Kovalchuk et al. (2008); Chen et al. (2010); Salter et al.(2008); Xin et al.(2009) "
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    • "Studies involving more than 2 groups were analyzed by 1-way ANOVA with Tukey's post-test; all others were subjected to unpaired Student's t-test (GraphPad Prism V.4) as previously described [36], [39], [40]. For pathway analysis, data processing and statistics were carried out as we have described [41]. Using Bioconductor, present (P), absent (A) or marginal (M) calls were determined using an MAS5 algorithm. "
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    • "Of note, we found down-regulation of miR-200 and miR-303, which are involved in resistance to doxorubicin (79), as was a known mediator of paclitaxel resistance, miR-302 (80,81). We also found changes in microRNA associated with endocrine therapy resistance, including RWJ67657-altered expression of miR-199, a known effector of fulvestrant resistance, and miR-328, associated with resistance to both fulvestrant and mitoxantrone (81,82). Thus, MCF-7TN-R-misexpressed microRNAs likely contribute to resistance to doxorubicin, paclitaxel and fulvestrant, in addition to their more general alterations associated with the anticancer effects of RWJ67657. "
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