MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients
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Leticia De Mattos-Arruda1,*, Giulia Bottai2,*, Paolo G. Nuciforo3, Luca Di Tommaso4, Elisa Giovannetti5,6, Vicente Peg7, Agnese Losurdo8, José Pérez-Garcia1, Giovanna Masci8, Fabio Corsi9, Javier Cortés1,10, Joan Seoane1,11, George A. Calin12,13, Libero Santarpia2
1Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
2Oncology Experimental Therapeutics Unit, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy
3Molecular Oncology Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain
4Division of Pathology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy, University of Milan, Milan, Italy
5Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
6Cancer Pharmacology Laboratory, AIRC Start-Up Unit, University of Pisa, Pisa, Italy
7Pathology Department, Vall d’Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain
8Division of Oncology and Hematology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy
9Deparment of Clinical and Biomedical Sciences “Luigi Sacco”, University of Milan, Milan, Italy
10Ramon y Cajal University Hospital, Madrid, Spain
11Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
12Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
13Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*These authors have contributed equally to this work
Libero Santarpia, e-mail: [email protected] or e-mail: [email protected]
Keywords: HER2-overexpressing breast cancers, microRNA-21, resistance to neoadjuvant trastuzumab-chemotherapy, epithelial-to-mesenchymal transition, tumor-associated immune response
Received: June 25, 2015 Accepted: September 25, 2015 Published: October 07, 2015
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.
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