Erythropoietin drives breast cancer progression by activation of its receptor EPOR

Ka-Kui Chan, Kyle B Matchett, Jonathan A Coulter, Hiu-Fung Yuen, Cian M McCrudden, Shu-Dong Zhang, Gareth W Irwin, Matthew A Davidson, Thomas Rülicke, Sophie Schober, Ludger Hengst, Heidelinde Jaekel, Angela Platt-Higgins, Philip S Rudland, Ken I Mills, Perry Maxwell, Mohamed El-Tanani, Terence R Lappin

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages38251-38263
Number of pages13
JournalOncotarget
Volume8
Issue number24
DOIs
Publication statusPublished - 18 Mar 2017

Fingerprint

Erythropoietin
Breast Neoplasms
Erythropoietin Receptors
Neoplasms
Phosphatidylinositol 3-Kinases
Down-Regulation
Growth
Heterologous Transplantation
Blood Transfusion
Anemia
Erythrocytes
Cell Proliferation
Apoptosis
Cell Line
Survival
Therapeutics

Keywords

  • EPO
  • EPOR
  • breast cancer
  • MYC
  • apoptosis

Cite this

Chan, K-K., Matchett, K. B., Coulter, J. A., Yuen, H-F., McCrudden, C. M., Zhang, S-D., ... Lappin, T. R. (2017). Erythropoietin drives breast cancer progression by activation of its receptor EPOR. Oncotarget, 8(24), 38251-38263. https://doi.org/10.18632/oncotarget.16368
Chan, Ka-Kui ; Matchett, Kyle B ; Coulter, Jonathan A ; Yuen, Hiu-Fung ; McCrudden, Cian M ; Zhang, Shu-Dong ; Irwin, Gareth W ; Davidson, Matthew A ; Rülicke, Thomas ; Schober, Sophie ; Hengst, Ludger ; Jaekel, Heidelinde ; Platt-Higgins, Angela ; Rudland, Philip S ; Mills, Ken I ; Maxwell, Perry ; El-Tanani, Mohamed ; Lappin, Terence R. / Erythropoietin drives breast cancer progression by activation of its receptor EPOR. In: Oncotarget. 2017 ; Vol. 8, No. 24. pp. 38251-38263.
@article{4b04698518c1498bb65c974af0f0206a,
title = "Erythropoietin drives breast cancer progression by activation of its receptor EPOR",
abstract = "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.",
keywords = "EPO, EPOR, breast cancer, MYC, apoptosis",
author = "Ka-Kui Chan and Matchett, {Kyle B} and Coulter, {Jonathan A} and Hiu-Fung Yuen and McCrudden, {Cian M} and Shu-Dong Zhang and Irwin, {Gareth W} and Davidson, {Matthew A} and Thomas R{\"u}licke and Sophie Schober and Ludger Hengst and Heidelinde Jaekel and Angela Platt-Higgins and Rudland, {Philip S} and Mills, {Ken I} and Perry Maxwell and Mohamed El-Tanani and Lappin, {Terence R}",
year = "2017",
month = "3",
day = "18",
doi = "10.18632/oncotarget.16368",
language = "English",
volume = "8",
pages = "38251--38263",
journal = "Oncotarget",
issn = "1949-2553",
number = "24",

}

Chan, K-K, Matchett, KB, Coulter, JA, Yuen, H-F, McCrudden, CM, Zhang, S-D, Irwin, GW, Davidson, MA, Rülicke, T, Schober, S, Hengst, L, Jaekel, H, Platt-Higgins, A, Rudland, PS, Mills, KI, Maxwell, P, El-Tanani, M & Lappin, TR 2017, 'Erythropoietin drives breast cancer progression by activation of its receptor EPOR', Oncotarget, vol. 8, no. 24, pp. 38251-38263. https://doi.org/10.18632/oncotarget.16368

Erythropoietin drives breast cancer progression by activation of its receptor EPOR. / Chan, Ka-Kui; Matchett, Kyle B; Coulter, Jonathan A; Yuen, Hiu-Fung; McCrudden, Cian M; Zhang, Shu-Dong; Irwin, Gareth W; Davidson, Matthew A; Rülicke, Thomas; Schober, Sophie; Hengst, Ludger; Jaekel, Heidelinde; Platt-Higgins, Angela; Rudland, Philip S; Mills, Ken I; Maxwell, Perry; El-Tanani, Mohamed; Lappin, Terence R.

In: Oncotarget, Vol. 8, No. 24, 18.03.2017, p. 38251-38263.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Erythropoietin drives breast cancer progression by activation of its receptor EPOR

AU - Chan, Ka-Kui

AU - Matchett, Kyle B

AU - Coulter, Jonathan A

AU - Yuen, Hiu-Fung

AU - McCrudden, Cian M

AU - Zhang, Shu-Dong

AU - Irwin, Gareth W

AU - Davidson, Matthew A

AU - Rülicke, Thomas

AU - Schober, Sophie

AU - Hengst, Ludger

AU - Jaekel, Heidelinde

AU - Platt-Higgins, Angela

AU - Rudland, Philip S

AU - Mills, Ken I

AU - Maxwell, Perry

AU - El-Tanani, Mohamed

AU - Lappin, Terence R

PY - 2017/3/18

Y1 - 2017/3/18

N2 - 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.

AB - 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.

KW - EPO

KW - EPOR

KW - breast cancer

KW - MYC

KW - apoptosis

UR - https://pure.ulster.ac.uk/en/publications/erythropoietin-drives-breast-cancer-progression-by-activation-of--3

U2 - 10.18632/oncotarget.16368

DO - 10.18632/oncotarget.16368

M3 - Article

VL - 8

SP - 38251

EP - 38263

JO - Oncotarget

T2 - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 24

ER -

Chan K-K, Matchett KB, Coulter JA, Yuen H-F, McCrudden CM, Zhang S-D et al. Erythropoietin drives breast cancer progression by activation of its receptor EPOR. Oncotarget. 2017 Mar 18;8(24):38251-38263. https://doi.org/10.18632/oncotarget.16368