Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy

Matilde Todaro, Alice Turdo, Monica Bartucci, Flora Iovino, Rosanna Dattilo, Marco Biffoni, Giorgio Stassi, Giulia Federici, Ruggero De Maria, Ann Zeuner

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6393-6400
Number of pages8
JournalCancer Research
Volume73
Issue number21
DOIs
Publication statusPublished - Nov 1 2013

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Neoplastic Stem Cells
Erythropoietin
Cell Survival
Breast Neoplasms
Drug Therapy
Neoplasms
Hematinics
Survival
Erythropoietin Receptors
Cytoprotection
MAP Kinase Signaling System
Drug Resistance
Heterografts
Anemia
Therapeutics
Clinical Trials
Recurrence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Todaro, M., Turdo, A., Bartucci, M., Iovino, F., Dattilo, R., Biffoni, M., ... Zeuner, A. (2013). Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy. Cancer Research, 73(21), 6393-6400. https://doi.org/10.1158/0008-5472.CAN-13-0248

Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy. / Todaro, Matilde; Turdo, Alice; Bartucci, Monica; Iovino, Flora; Dattilo, Rosanna; Biffoni, Marco; Stassi, Giorgio; Federici, Giulia; De Maria, Ruggero; Zeuner, Ann.

In: Cancer Research, Vol. 73, No. 21, 01.11.2013, p. 6393-6400.

Research output: Contribution to journalArticle

Todaro, M, Turdo, A, Bartucci, M, Iovino, F, Dattilo, R, Biffoni, M, Stassi, G, Federici, G, De Maria, R & Zeuner, A 2013, 'Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy', Cancer Research, vol. 73, no. 21, pp. 6393-6400. https://doi.org/10.1158/0008-5472.CAN-13-0248
Todaro, Matilde ; Turdo, Alice ; Bartucci, Monica ; Iovino, Flora ; Dattilo, Rosanna ; Biffoni, Marco ; Stassi, Giorgio ; Federici, Giulia ; De Maria, Ruggero ; Zeuner, Ann. / Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy. In: Cancer Research. 2013 ; Vol. 73, No. 21. pp. 6393-6400.
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