title: MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients.
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.
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: De Mattos-Arruda
authors.affiliation: Oncology Experimental Therapeutics Unit, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bottai
authors.affiliation: Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Nuciforo
authors.affiliation: Division of Pathology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy, University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.|Cancer Pharmacology Laboratory, AIRC Start-Up Unit, University of Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: Pathology Department, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.affiliation: Division of Oncology and Hematology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Losurdo
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Pérez-Garcia
authors.affiliation: Division of Oncology and Hematology, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masci
authors.affiliation: Deparment of Clinical and Biomedical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsi
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.|Ramon y Cajal University Hospital, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Oncology Experimental Therapeutics Unit, IRCCS Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D015850:Interleukin-6; D035683:MicroRNAs; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D058539:Phosphatidylinositol 3-Kinase; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000068878:Trastuzumab; C508600:IL6 protein, human; C524940:MIRN21 microRNA, human; C114487:PDCD4 protein, human; C494086:STAT3 protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human
keywords: HER2-overexpressing breast cancers; epithelial-to-mesenchymal transition; microRNA-21; resistance to neoadjuvant trastuzumab-chemotherapy; tumor-associated immune response