Abstract
<div>Abstract<p><b>Purpose:</b> Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study.</p><p><b>Experimental Design:</b> Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays <i>in vitro</i> (two-dimensional/three-dimensional growth and survival) and <i>in vivo</i> (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents.</p><p><b>Results:</b> A large variation in EPOR expression across cell lines was observed. <i>In vitro</i>, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (<i>P</i> < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. <i>In vivo</i>, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (<i>P</i> < 0.05).</p><p><b>Conclusions:</b> The lack of an <i>in vitro</i> effect of rHuEPO highlights the importance of <i>in vivo</i> studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy. <i>Clin Cancer Res; 17(19); 6151–62. ©2011 AACR</i>.</p></div>
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