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MicroRNA-125b upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer

Overview of attention for article published in Breast Cancer Research, January 2015
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Title
MicroRNA-125b upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer
Published in
Breast Cancer Research, January 2015
DOI 10.1186/s13058-015-0515-1
Pubmed ID
Authors

Paul Vilquin, Caterina F Donini, Marie Villedieu, Evelyne Grisard, Laura Corbo, Thomas Bachelot, Julie A Vendrell, Pascale A Cohen

Abstract

IntroductionIncreasing evidence indicates micro RNAs (miRNAs) being important players in oncogenesis. Considering the wide-spread use of aromatase inhibitors (AIs) in endocrine therapy as a first-line treatment for post-menopausal endocrine receptor ¿-positive breast cancer patients, identifying deregulated expression levels of miRNAs in association with AI resistance is of utmost importance.MethodsTo gain further insight into the molecular mechanisms underlying the AI resistance, we performed miRNA microarray experiments using a new model of acquired resistance to letrozole (Res-Let cells), obtained by long-term exposure of aromatase-overexpressing MCF-7 cells (MCF-7aro cells) to letrozole, and a model of acquired anastrozole resistance (Res-Ana cells). Three miRNAs (miR-125b, miR-205 and miR-424) similarly deregulated in both AI-resistant cell lines were then investigated in terms of their functional role in AI resistance development, breast cancer cell aggressiveness and their clinical relevance using a cohort of 65 primary breast tumor samples.ResultsWe identified the deregulated expression of 33 miRNAs in Res-Let cells and of 18 miRNAs in Res-Ana cells compared to the sensitive MCF-7aro cell line. The top-ranked Kyoto Encyclopedia of Genes and Genomes pathways delineated by both miRNA signatures converged on the AKT pathway, which was found constitutively activated in both AI-resistant cell lines. We report for the first time that ectopic overexpression of either miR-125b or miR-205, or the silencing of miR-424 expression in the sensitive MCF-7aro cell line were sufficient to confer resistance to letrozole and to anastrozole, to target and to activate the AKT/mTOR pathway, and to increase formation capacity of cancer-initiating-like cells possessing self-renewing properties. Increasing miR-125b expression levels was also sufficient to confer estrogen-independent growth properties to the sensitive MCF-7aro cell line. Finally, elevated miR-125b expression levels were a novel marker for poor prognosis in breast cancer, and targeting miR-125b in Res-Let cells overcame letrozole resistance.ConclusionThis study highlights that acquisition of specific deregulated miRNAs is a newly discovered alternative mechanism developed by AI-resistant breast cancer cells to achieve constitutive activation of the AKT/mTOR pathway and develop AI resistance. It also highlights that miR-125b is a new biomarker of poor prognosis and a candidate therapeutic target of AI-resistant breast cancers.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 49 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 2%
Unknown 48 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 12 24%
Researcher 10 20%
Student > Master 8 16%
Student > Doctoral Student 3 6%
Student > Bachelor 3 6%
Other 7 14%
Unknown 6 12%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 21 43%
Medicine and Dentistry 10 20%
Agricultural and Biological Sciences 6 12%
Computer Science 1 2%
Psychology 1 2%
Other 2 4%
Unknown 8 16%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 February 2015.
All research outputs
#3,935,393
of 4,698,042 outputs
Outputs from Breast Cancer Research
#679
of 792 outputs
Outputs of similar age
#132,147
of 164,336 outputs
Outputs of similar age from Breast Cancer Research
#39
of 45 outputs
Altmetric has tracked 4,698,042 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 792 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.7. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 45 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.