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

Oncotarget. 2015 Nov 10;6(35):37269-80. doi: 10.18632/oncotarget.5495.

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.

Keywords: HER2-overexpressing breast cancers; epithelial-to-mesenchymal transition; microRNA-21; resistance to neoadjuvant trastuzumab-chemotherapy; tumor-associated immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Disease Progression
  • Drug Resistance, Neoplasm* / genetics
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NF-kappa B / metabolism
  • Neoadjuvant Therapy*
  • Neoplasm, Residual
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • RNA Interference
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Transfection
  • Trastuzumab / therapeutic use*
  • Treatment Outcome
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-6
  • MIRN21 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • PDCD4 protein, human
  • RNA-Binding Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Phosphatidylinositol 3-Kinase
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Trastuzumab