title: Recombinant human erythropoietin in combination with chemotherapy increases breast cancer metastasis in preclinical mouse models.
abstract: OBJECTIVE
  Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study.
  
  
  METHODS
  Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents.
  
  
  RESULTS
  A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05).
  
  
  CONCLUSIONS
  The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy.
authors.affiliation: Division of Hematology, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Hedley
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Chu
authors.forename: D George
authors.initials: DG
authors.lastname: Ormond
authors.forename: Michel S
authors.initials: MS
authors.lastname: Beausoleil
authors.forename: Alexandra
authors.initials: A
authors.lastname: Boasie
authors.forename: Alison L
authors.initials: AL
authors.lastname: Allan
authors.forename: Anargyros
authors.initials: A
authors.lastname: Xenocostas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D004921:Erythropoietin