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
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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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    ABSTRACT: Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.
    PLoS ONE 08/2013; 8(8):e69291. DOI:10.1371/journal.pone.0069291 · 3.23 Impact Factor
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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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    ABSTRACT: Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF‑κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N‑cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR‑200, miR‑303, miR‑302, miR‑199 and miR‑328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.
    International Journal of Oncology 04/2013; 42(4):1139-50. DOI:10.3892/ijo.2013.1814 · 3.03 Impact Factor
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    • "B. tabaci Q has shown greater resistance to neonicotinoid and pyriproxyfen insecticides than B [47]–[49]. Accumulating evidence indicates an important role of miRNAs in drug resistance, and miRNA expression profiling is correlated with the development of drug resistance [79]–[81]. Although many studies have reported the involvement of miRNAs in drug resistance, few of these have concerned insects. "
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    ABSTRACT: MicroRNAs (miRNAs) are small, conserved, non-coding RNAs that post-transcriptionally regulate gene expression. Bemisia tabaci (Gennadius) B and Q are two invasive and dominant whiteflies, and B. tabaci Q has been displacing B in China. Differences in biological traits (fecundity, host range, resistance to insecticides, etc.) as affected by miRNAs might be involved in the displacement. In this study, we performed high-throughput sequencing to identify miRNAs in B. tabaci B and Q. We identified 170 conserved miRNAs and 15 novel candidates, and found significant differences in the expression of miRNAs between B. tabaci B and Q. Expression levels of miRNAs differ in B. tabaci B vs. Q. Additional research is needed to determine whether these differences are related to differences in the biology of B. tabaci B and Q, and whether these differences help explain why B. tabaci Q is displacing B in China.
    PLoS ONE 03/2013; 8(3):e59884. DOI:10.1371/journal.pone.0059884 · 3.23 Impact Factor
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