Recombinant Human Erythropoietin Antagonizes Trastuzumab Treatment of Breast Cancer Cells via Jak2-mediated Src Activation and PTEN Inactivation

Cancer Cell. 2010 Nov 16;18(5):423-35. doi: 10.1016/j.ccr.2010.10.025.

Abstract

We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Drug Antagonism
  • Drug Resistance, Neoplasm / drug effects
  • Enzyme Activation
  • Erythropoietin / pharmacology*
  • Erythropoietin / therapeutic use
  • Female
  • Humans
  • Janus Kinase 2 / physiology*
  • Mice
  • PTEN Phosphohydrolase / metabolism*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, Erythropoietin / chemistry
  • Receptors, Erythropoietin / metabolism
  • Recombinant Proteins
  • Signal Transduction
  • Transplantation, Heterologous
  • Trastuzumab

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Receptors, Erythropoietin
  • Recombinant Proteins
  • Erythropoietin
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • JAK2 protein, human
  • Janus Kinase 2
  • Proto-Oncogene Proteins pp60(c-src)
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Trastuzumab