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.

The Association between Dialysis Dose and Risk of Cancer Death in Patients Undergoing Hemodialysis: The Q-Cohort Study

“…There are several possible explanations for the link between ESAs and cancer risk. ESAs have been shown to increase tumor angiogenesis and growth and stimulate the tumor expression of erythropoietin receptors, which promote cancer proliferation, resulting in increased cancer death (32,33). Our current results support the suggestion that patients without ESAs have a lower risk of cancer death than those taking ESAs.…”

Erythropoietin and its derivatives: from tissue protection to immune regulation

“…EPOR signaling has been proved critical to tumor survival and proliferation. When EPOR signaling was blocked by EPOR knockdown or soluble EPOR against EPO, it inhibited tumor growth and invasion, and resulted in cell apoptosis 71,[75][76][77] . Interestingly, in most studies, EPO stimulation had no significant effects on tumor proliferation, survival or invasion under normoxia 69,[71][72][73][74]77,78 ; only in few cases, such as in melanoma, EPO was reported to stimulate tumor growth both in vivo and in vitro on eIF4Edependent pathway 79 .…”

Erythropoietin Signaling Increases Choroidal Macrophages and Cytokine Expression, and Exacerbates Choroidal Neovascularization

“…EPO has been proposed for its neuroprotective and anti-oxidative effects as a potential preventive treatment in various diseases, including in atrophic AMD 2 . However, there remain concerns about possible pathologic effects from other effects of EPO, including angiogenesis and its potential role in cancer progression 29 , 30 . In this study, we investigated the role of EPO/EPOR signaling in experimental CNV and explored the hypothesis that EPOR signaling would lead to the development of CNV.…”