Erythropoietin drives breast cancer progression by activation of its receptor EPOR
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Ka Kui Chan1,7,*, Kyle B. Matchett1,*, Jonathan A. Coulter2, Hiu-Fung Yuen1, Cian M. McCrudden2, Shu-Dong Zhang1,8, Gareth W. Irwin1, Matthew A. Davidson1, Thomas Rülicke3, Sophie Schober3, Ludger Hengst4, Heidelinde Jaekel4, Angela Platt-Higgins5, Philip S. Rudland5, Ken I. Mills1, Perry Maxwell6, Mohamed El-Tanani1,9,** and Terence R. Lappin1,**
1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7AE, UK
2 School of Pharmacy, Queen’s University Belfast, Belfast BT9 7AE, UK
3 Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna A-1210, Austria
4 Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck A-6020, Austria
5 Institute of Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK
6 Northern Ireland Molecular Pathology Laboratory, Belfast Health & Social Care Trust, Queen’s University Belfast, Belfast BT9 7AE, UK
7 Department of Pathology, The University of Hong Kong, Hong Kong Special Administrative Region Hong Kong 999077, China
8 Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, Londonderry BT47 6SB, UK
9 Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK
* Co-first author
** These authors have contributed equally to this work
Terence R. Lappin, email:
Keywords: EPO, EPOR, breast cancer, MYC, apoptosis
Received: February 10, 2017 Accepted: February 27, 2017 Published: March 18, 2017
Breast cancer is a leading cause of cancer-related deaths. Anemia is common in breast cancer patients and can be treated with blood transfusions or with recombinant erythropoietin (EPO) to stimulate red blood cell production. Clinical studies have indicated decreased survival in some groups of cancer patients treated with EPO. Numerous tumor cells express the EPO receptor (EPOR), posing a risk that EPO treatment would enhance tumor growth, but the mechanisms involved in breast tumor progression are poorly understood.
Here, we have examined the functional role of the EPO-EPOR axis in pre-clinical models of breast cancer. EPO induced the activation of PI3K/AKT and MAPK pathways in human breast cancer cell lines. EPOR knockdown abrogated human tumor cell growth, induced apoptosis through Bim, reduced invasiveness, and caused downregulation of MYC expression. EPO-induced MYC expression is mediated through the PI3K/AKT and MAPK pathways, and overexpression of MYC partially rescued loss of cell proliferation caused by EPOR downregulation. In a xenotransplantation model, designed to simulate recombinant EPO therapy in breast cancer patients, knockdown of EPOR markedly reduced tumor growth.
Thus, our experiments in vitro and in vivo demonstrate that functional EPOR signaling is essential for the tumor-promoting effects of EPO and underline the importance of the EPO-EPOR axis in breast tumor progression.
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