title: Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy.
abstract: Recombinant erythropoietin (EPO) analogs [erythropoiesis-stimulating agents (ESA)] are clinically used to treat anemia in patients with cancer receiving chemotherapy. After clinical trials reporting increased adverse events and/or reduced survival in ESA-treated patients, concerns have been raised about the potential role of ESAs in promoting tumor progression, possibly through tumor cell stimulation. However, evidence is lacking on the ability of EPO to directly affect cancer stem-like cells, which are thought to be responsible for tumor progression and relapse. We found that breast cancer stem-like cells (BCSC) isolated from patient tumors express the EPO receptor and respond to EPO treatment with increased proliferation and self-renewal. Importantly, EPO stimulation increased BCSC resistance to chemotherapeutic agents and activated cellular pathways responsible for survival and drug resistance. Specifically, the Akt and ERK pathways were activated in BCSC at early time points following EPO treatment, whereas Bcl-xL levels increased at later times. In vivo, EPO administration counteracted the effects of chemotherapeutic agents on BCSC-derived orthotopic tumor xenografts and promoted metastatic progression both in the presence and in the absence of chemotherapy treatment. Altogether, these results indicate that EPO acts directly on BCSC by activating specific survival pathways, resulting in BCSC protection from chemotherapy and enhanced tumor progression.
authors.affiliation: Authors' Affiliations: Department of Surgical and Oncological Sciences, University of Palermo, Palermo; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità; Department of Surgical Sciences, University La Sapienza; and National Cancer Institute Regina Elena, Rome, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Alice
authors.initials: A
authors.lastname: Turdo
authors.forename: Monica
authors.initials: M
authors.lastname: Bartucci
authors.forename: Flora
authors.initials: F
authors.lastname: Iovino
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dattilo
authors.forename: Marco
authors.initials: M
authors.lastname: Biffoni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.forename: Giulia
authors.initials: G
authors.lastname: Federici
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.forename: Ann
authors.initials: A
authors.lastname: Zeuner
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004921:Erythropoietin