Scopus: 78 citas, Google Scholar: citas,
MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients
De Mattos-Arruda, Leticia (Institut d'Oncologia de la Vall Hebron)
Bottai, Giulia (Oncology Experimental Therapeutics Unit. IRCCS Humanitas Clinical and Research Institute (Italy))
Nuciforo, Paolo Giovanni (Institut d'Oncologia de la Vall Hebron)
Di Tommaso, Luca (Division of Pathology. IRCCS Humanitas Clinical and Research Institute (Italy))
Giovannetti, Elisa (University of Pisa. Cancer Pharmacology Laboratory. AIRC Start-Up Unit (Italy))
Peg, Vicente (Hospital Universitari Vall d'Hebron. Departament de Patologia)
Losurdo, Agnese (Division of Oncology and Hematology. IRCCS Humanitas Clinical and Research Institute (Italy))
Pérez-Garcia, José (Institut d'Oncologia de la Vall Hebron)
Masci, Giovanna (Division of Oncology and Hematology. IRCCS Humanitas Clinical and Research Institute (Italy))
Corsi, Fabio (University of Milan. Deparment of Clinical and Biomedical Sciences "Luigi Sacco" (Italy))
Cortés, Javier (Hospital Universitario Ramón y Cajal)
Seoane Suárez, Joan (Institut d'Oncologia de la Vall Hebron)
Calin, George A. (The University of Texas MD Anderson Cancer Center (USA))
Santarpia, Libero (Oncology Experimental Therapeutics Unit. IRCCS Humanitas Clinical and Research Institute (Italy))
Universitat Autònoma de Barcelona

Fecha: 2015
Resumen: 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.
Derechos: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Lengua: Anglès.
Documento: article ; recerca ; publishedVersion
Materia: HER2-overexpressing breast cancers ; MicroRNA-21 ; Resistance to neoadjuvant trastuzumab-chemotherapy ; Epithelial-to-mesenchymal transition ; Tumor-associated immune response
Publicado en: Oncotarget, Vol. 6, Num. 35 (October 2015) , p. 37269-37280, ISSN 1949-2553

PMID: 26452030
DOI: 10.18632/oncotarget.5495

12 p, 2.2 MB

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