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 (Vall d'Hebron Institut d'Oncologia)
Bottai, Giulia (Oncology Experimental Therapeutics Unit. IRCCS Humanitas Clinical and Research Institute (Italy))
Nuciforo, Paolo (Vall d'Hebron Institut d'Oncologia)
Di Tommaso, Luca (IRCCS Humanitas Clinical and Research Institute (Itàlia))
Giovannetti, Elisa (University of Pisa. Cancer Pharmacology Laboratory. AIRC Start-Up Unit (Italy))
Peg, Vicente (Hospital Universitari Vall d'Hebron)
Losurdo, Agnese (IRCCS Humanitas Clinical and Research Institute (Itàlia). Division of Oncology and Hematology)
Pérez-Garcia, José (Vall d'Hebron Institut d'Oncologia)
Masci, Giovanna (IRCCS Humanitas Clinical and Research Institute (Itàlia). Division of Oncology and Hematology)
Corsi, Fabio (University of Milan. Deparment of Clinical and Biomedical Sciences "Luigi Sacco" (Italy))
Cortés, Javier (Hospital Universitario Ramón y Cajal (Madrid))
Seoane Suárez, Joan (Vall d'Hebron Institut d'Oncologia)
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

Date:	2015
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.
Rights:	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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	HER2-overexpressing breast cancers ; MicroRNA-21 ; Resistance to neoadjuvant trastuzumab-chemotherapy ; Epithelial-to-mesenchymal transition ; Tumor-associated immune response
Published in:	Oncotarget, Vol. 6, Num. 35 (October 2015) , p. 37269-37280, ISSN 1949-2553

DOI: 10.18632/oncotarget.5495
PMID: 26452030

12 p, 2.2 MB

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