title: EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation.
abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα(+)) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden; CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Susann
authors: S
authors: Reinbothe
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden; CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Anna-Maria
authors: AM
authors: Larsson
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden; CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Marica
authors: M
authors: Vaapil
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden; CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Caroline
authors: C
authors: Wigerup
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden.
authors: Jianmin
authors: J
authors: Sun
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden; CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Annika
authors: A
authors: Jögi
authors: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Drorit
authors: D
authors: Neumann
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden.
authors: Lars
authors: L
authors: Rönnstrand
authors: Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund, Sweden; CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: sven.pahlman@med.lu.se.
authors: Sven
authors: S
authors: Påhlman
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004921:Erythropoietin / Q000235:genetics / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt
keywords: Breast cancer; Erythropoietin receptor; Estrogen receptor; Proliferation