Effects of recombinant erythropoietin on breast cancer-initiating cells

Neoplasia. 2007 Dec;9(12):1122-9. doi: 10.1593/neo.07694.


Background: Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs). In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway.

Methods: In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR), CD24, CD44, Jagged-1 expression, and activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays.

Results: EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo) increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and PI3-kinase blocked both effects.

Conclusions: Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.

Keywords: CD24-/low/CD44+ breast cancer cells; Epor; Notch; breast cancer-initiating cells; rhEpo.

Publication types

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

MeSH terms

  • Adenocarcinoma / chemistry
  • Adenocarcinoma / pathology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / physiology
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / pathology*
  • Cell Adhesion / drug effects
  • Cell Division / drug effects
  • Chromones / pharmacology
  • Erythropoietin / adverse effects
  • Erythropoietin / pharmacology*
  • Female
  • Humans
  • Hyaluronan Receptors / biosynthesis
  • Hyaluronan Receptors / genetics
  • Morpholines / pharmacology
  • Neoplasm Proteins / agonists*
  • Neoplasm Proteins / physiology
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / physiology
  • Receptors, Erythropoietin / agonists*
  • Receptors, Erythropoietin / physiology
  • Recombinant Fusion Proteins / physiology
  • Recombinant Proteins
  • Sialic Acid Binding Ig-like Lectin 2 / biosynthesis
  • Sialic Acid Binding Ig-like Lectin 2 / genetics
  • Spheroids, Cellular / drug effects
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology


  • CD22 protein, human
  • CD44 protein, human
  • Chromones
  • Hyaluronan Receptors
  • Morpholines
  • NOTCH1 protein, human
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor, Notch1
  • Receptors, Erythropoietin
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Sialic Acid Binding Ig-like Lectin 2
  • Erythropoietin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Amyloid Precursor Protein Secretases