Abstract 548: Erythropoietin promotes mammary tumor development in MMTV-erbB-2 transgenic mice

Abstract

Abstract Erythropoietin (EPO), a cytokine that stimulates erythropoiesis, is frequently used to treat anemia in cancer patients. Recent clinical studies indicate that EPO administration might be associated with tumor progression and reduced overall survival rate. However, the mechanisms of EPO associated risk in cancer patients remain poorly understood. In particular, a spontaneous tumor model that allows us to test the effects of EPO on tumor development/progression and provide mechanistic insights into multifactoral interactions in a physiological context has not been established. In this study, we used the MMTV-erbB-2 transgenic mouse model to test the specific effect of EPO on erbB-2 overexpressing breast cancers and aimed to establish a spontaneous tumor model for relevant studies. Female erbB-2 transgenic mice were injected with EPO? at 2000 U/Kg body weight, twice a week for three weeks (between week 20 and 22). We found that EPO treatment during the premalignant risk window not only increased hemoglobin levels but also significantly promoted mammary tumor development. In contrast to a 36-week mean latency of tumor development in control group, the mean latency for EPO exposed mice was 30 weeks. Moreover, EPO exposure resulted in increased pulmonary metastasis. Whole mount analysis of mammary gland at 23 weeks showed that EPO exposure induced ductal branching and alveolar outgrowth, which was consistent with increased BrdU incorporation in EPO exposed mammary tissues. Molecular analysis of mammary tissues at 23 weeks showed that the protein levels of p-Jak2, p-erbB-2, p-Erk and p-Akt1 were significantly increased, which was accompanied by increased expression of EGFR, erbB-3, IGFR, Bcl-2, cyclin D1 and VEGF. These data suggest that EPO exposure induced the activation of both EPOR/Jak2 and erbB-2/EGFR/erbB-3 pathways, and had a broad impact on signal transduction and gene expression in mammary tissues. Although the difference in signal transduction and gene expression of tumor tissues between control and EPO exposed groups was less significant, tumors from EPO treated mice showed increased microvessel density as compared to controls, suggesting EPO exposure induced a long lasting proangiogenic effect. Consistently, conditioned medium extracted from EPO treated mammary tissues at 23 weeks significantly increased tube formation of endothelial cells. Taken together, our results demonstrate that EPO treatment promotes the development and metastasis of erbB-2 overexpressing mammary tumors and established the MMTV-erbB-2 mouse model for the studies of EPO associated cancer risk. The underlying mechanisms involve enhanced activation of erbB-2 pathway through EPOR/Jak2 activation and increased proangiogenic activities in EPO exposed mammary tissues. Since erbB-2 is overexpressed in about 30% of human breast cancers, these data will have significant impact on safe use of EPO in breast cancer patients with anemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 548. doi:1538-7445.AM2012-548