HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule A and B expression in human breast cancer cell lines

J Immunol. 2012 Mar 1;188(5):2136-45. doi: 10.4049/jimmunol.1102237. Epub 2012 Feb 1.


Overexpression of the receptor tyrosine kinases HER2 and HER3 is associated with a poor prognosis in several types of cancer. Presently, HER2- as well as HER3-targeted therapies are in clinical practice or evaluated within clinical trials, including treatment with mAbs mediating growth inhibition and/or activation of Ab-induced innate or adaptive cellular immunity. A better understanding of how HER2/HER3 signaling in tumors influences cellular immune mechanisms is therefore warranted. In this study, we demonstrate that HER2/HER3 signaling regulates the expression of MHC class I-related chain A and B (MICA and MICB) in breast cancer cell lines. The MICA and MICB (MICA/B) molecules act as key ligands for the activating receptor NK group 2, member D (NKG2D) and promote NK cell-mediated recognition and cytolysis. Genetic silencing of HER3 but not HER2 downregulated the expression of MICA/B, and HER3 overexpression significantly enhanced MICA expression. Among the major pathways activated by HER2/HER3 signaling, the PI3K/AKT pathway was shown to predominantly regulate MICA/B expression. Treatment with the HER3-specific ligand neuregulin 1β promoted the expression in a process that was antagonized by pharmacological and genetic interference with HER3 but not by the ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related protein kinases inhibitor caffeine. These observations further emphasize that HER2/HER3 signaling directly, and not via genotoxic stress, regulates MICA/B expression. As anticipated, stimulating HER2/HER3 enhanced the NKG2D-MICA/B-dependent NK cell-mediated cytotoxicity. Taken together, we conclude that signaling via the HER2/HER3 pathway in breast carcinoma cell lines may lead to enhanced NKG2D-MICA/B recognition by NK cells and T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology*
  • Cell Line, Tumor
  • Cytotoxicity Tests, Immunologic* / methods
  • Female
  • Gene Expression Regulation, Neoplastic / immunology
  • Histocompatibility Antigens Class I / biosynthesis*
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • MAP Kinase Signaling System / immunology
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / physiology*
  • Receptor, ErbB-3 / biosynthesis
  • Receptor, ErbB-3 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / enzymology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / pathology
  • Tumor Escape / genetics


  • Histocompatibility Antigens Class I
  • MHC class I-related chain A
  • MICB antigen
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Receptor, ErbB-3