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Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation.

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.

Pubmed ID: 21075308


  • Liang K
  • Esteva FJ
  • Albarracin C
  • Stemke-Hale K
  • Lu Y
  • Bianchini G
  • Yang CY
  • Li Y
  • Li X
  • Chen CT
  • Mills GB
  • Hortobagyi GN
  • Mendelsohn J
  • Hung MC
  • Fan Z


Cancer cell

Publication Data

November 16, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA016672
  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: P50 CA098258
  • Agency: NCI NIH HHS, Id: R01 CA129036
  • Agency: NCI NIH HHS, Id: R01 CA129036
  • Agency: NCI NIH HHS, Id: R01 CA129036-01A1
  • Agency: NCI NIH HHS, Id: R01 CA129036-02
  • Agency: NCI NIH HHS, Id: R01 CA129036-03

Mesh Terms

  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols
  • Breast Neoplasms
  • Drug Antagonism
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Erythropoietin
  • Female
  • Humans
  • Janus Kinase 2
  • Mice
  • PTEN Phosphohydrolase
  • Proto-Oncogene Proteins pp60(c-src)
  • Receptor, ErbB-2
  • Receptors, Erythropoietin
  • Recombinant Proteins
  • Signal Transduction
  • Transplantation, Heterologous