Evidence map›Paper›PMID 26452030›Full record

ArticleOncotarget2015

MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients.

Leticia De Mattos-Arruda, Giulia Bottai, Paolo G Nuciforo, Luca Di Tommaso, Elisa Giovannetti, Vicente Peg, Agnese Losurdo, José Pérez-Garcia, Giovanna Masci, Fabio Corsi and 4 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
98citing papers in PubMed, 3 pooled it
9.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

98 citing papers in PubMed, 3 syntheses or guidelines pooled it, 150 citations in OpenAlex.

  1. Pooled it
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  9. The mechanism of ncRNA in trastuzumab resistance in HER2-positive tumors.Medical oncology (Northwood, London, England) · 2025
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  14. The Impact of Pdcd4, a Translation Inhibitor, on Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2024
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38 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 8 institutions in 4 countries.

Leticia De Mattos-ArrudaVall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Giulia BottaiOncology Experimental Therapeutics Unit, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
Paolo G NuciforoMolecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Luca Di TommasoDivision of Pathology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy, University of Milan, Milan, Italy.
Elisa GiovannettiDepartment of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Vicente PegPathology Department, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
Agnese LosurdoDivision of Oncology and Hematology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
José Pérez-GarciaVall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Giovanna MasciDivision of Oncology and Hematology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
Fabio CorsiDeparment of Clinical and Biomedical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
Javier CortésVall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Joan SeoaneVall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
George A CalinDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Libero SantarpiaOncology Experimental Therapeutics Unit, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
Universitat Autònoma de Barcelona · ESHumanitas University · ITIstituti di Ricovero e Cura a Carattere Scientifico · ITUniversity of Milan · ITInstitució Catalana de Recerca i Estudis Avançats · ESThe University of Texas MD Anderson Cancer Center · USUniversity of Pisa · ITVall d'Hebron Institute of Oncology

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Patients with primary HER2-positive breast cancer benefit from HER2-targeted therapies. Nevertheless, a significant proportion of these patients die of disease progression due to mechanisms of drug resistance. MicroRNAs (miRNAs) are emerging as critical core regulators of drug resistance that act by modulating the epithelial-to-mesenchymal transition (EMT) and cancer-related immune responses. In this study, we investigated the association between the expression of a specific subset of 14 miRNAs involved in EMT processes and immune functions and the response to neoadjuvant trastuzumab and chemotherapy in 52 patients with HER2-overexpressing breast tumors. The expression of only a single miRNA, miR-21, was significantly associated with residual disease (p = 0.030) and increased after trastuzumab-chemotherapy (p = 0.012). A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN (rs = -0.502; p = 0.005) and PDCD4 (rs = -0.426; p = 0.019), which differentially influenced the drug sensitivity of HER2-positive breast cancer cells. However, PTEN expression was only marginally associated with residual disease. We further demonstrated that miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-κB-mediated signaling loop and activating the PI3K pathway. Our findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer. Collectively, these data provide a rationale for using miR-21 expression as a biomarker to select trastuzumab-chemotherapy-resistant HER2-positive breast cancer patients who may benefit from treatments containing PI3K inhibitors or immunomodulatory drugs.

Indexed as

Drug Resistance, NeoplasmEpithelial-Mesenchymal TransitionNeoadjuvant TherapyAntineoplastic AgentsApoptosis Regulatory ProteinsBreast NeoplasmsCell Line, TumorChemotherapy, AdjuvantDisease ProgressionErb-b2 Receptor Tyrosine KinasesFemaleGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticHumansInflammation MediatorsInterleukin-6Antineoplastic AgentsApoptosis Regulatory ProteinsERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesIL6 protein, humanInflammation MediatorsInterleukin-6MicroRNAsMIRN21 microRNA, humanNF-kappa BPDCD4 protein, humanPhosphatidylinositol 3-KinasePTEN PhosphohydrolasePTEN protein, humanRNA-Binding ProteinsSTAT3 protein, humanSTAT3 Transcription FactorTrastuzumabepithelial-to-mesenchymal transitionHER2-overexpressing breast cancersmicroRNA-21resistance to neoadjuvant trastuzumab-chemotherapytumor-associated immune response

Identifiers

PMID26452030
PMCPMC4741929
OpenAlexW1771120914

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.