Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor–positive breast carcinoma models

Abstract

We investigated the significance of erythropoietin receptor (EPOR) expression following treatment with recombinant human erythropoietin (rHuEPO; epoetin A) and the effect of recombinant epoetins (epoetin A, epoetin B, and darbepoetin A) alone or in combination with anticancer therapy on tumor growth in two well-established preclinical models of breast carcinoma (MDA-MB-231 and MCF-7 cell lines). Expression and localization of EPOR under hypoxic and normoxic conditions in MDA-MB-231 and MCF-7 cells were evaluated by immunoblotting, flow cytometry, and immunohistochemistry. EPOR binding was evaluated using [125 I]rHuEPO. Proliferation, migration, and signaling in MDA-MB-231 and MCF-7 cells following treatment with rHuEPO were evaluated. Tumor growth was assessed following administration of recombinant epoetins alone and in combination with paclitaxel (anticancer therapy) in orthotopically implanted MDA-MB-231 and MCF-7 breast carcinoma xenograft models in athymic mice. EPOR expression was detected in both tumor cell lines. EPOR localization was found to be exclusively cytosolic and no specific [ 125 I]rHuEPO binding was observed. There was no stimulated migration, proliferation, or activation of mitogen-activated protein kinase and AKT following rHuEPO treatment. In mice, treatment with recombinant epoetins alone and in combination with paclitaxel resulted in equivalent tumor burdens compared with vehicle-treated controls. Results from our study suggest that although EPOR expression was observed in two well-established breast carcinoma cell lines, it was localized to a cytosolic distribution and did not transduce a signaling cascade in tumors that leads to tumor growth. The addition of recombinant epoetins to paclitaxel did not affect the outcome of paclitaxel therapy in breast carcinoma xenograft models. These results show that recombinant epoetins do not evoke a physiologic response on EPOR-bearing tumor cells as assessed by numerous variables, including growth, migration, and cytotoxic challenge in preclinical in vivo tumor models. [Mol Cancer Ther 2006;5(2):347 -55]

Anemia Management in Oncology and Hematology

“…Furthermore, a number of other studies have shown that EPO does not stimulate tumor growth in vitro or in vivo. Recombinant EPO did not stimulate tumor growth in xenografted mouse tumors [35] and potentiated the positive effects of radiation therapy [36]. Retrospective studies also showed that recombinant EPO prolonged survival in myelodysplastic syndrome (MDS) patients and did not accelerate leukemic transformation [37].…”

Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line

“…The biological effects of Epo stimulation of tumor cells is still debated with reports of enhanced survival (8,11), proliferation (4,6,(38)(39)(40), resistance to treatment (38,41,42), tumor angiogenesis (43)(44)(45), chemotaxis (46), invasion (47)(48)(49)(50), and migration (40,46,51). Others have reported no discernible effects of Epo (52).…”

Human recombinant erythropoietin does not promote cancer growth in presence of functional receptors expressed in cancer cells

“…[25][26] Indeed, EPOR activation has been observed in the absence of any modification in growth rate. 27 It may be that EPO-EPOR signaling effects on proliferative and anti-apoptotic pathways are dependent on the biochemical context of each cellular model and therefore must be assessed independently.…”