Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models.
We investigated the significance of erythropoietin receptor (EPOR) expression following treatment with recombinant human erythropoietin (rHuEPO; epoetin alpha) and the effect of recombinant epoetins (epoetin alpha, epoetin beta, and darbepoetin alpha) 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 [125I]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 [125I]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.
LaMontagne
Kenneth R
KR
Drug Discovery, Growth Factors, Johnson and Johnson Pharmaceutical Research and Development, Room B354, OMP Building, 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA. klamontagne@prdus.jnj.com
Butler
Jeannene
J
Marshall
Deborah J
DJ
Tullai
Jennifer
J
Gechtman
Ze'ev
Z
Hall
Chassidy
C
Meshaw
Alan
A
Farrell
Francis X
FX
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D002277:Carcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004921:Erythropoietin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000032:analysis / Q000378:metabolism*; D011994:Recombinant Proteins; D023041:Xenograft Model Antitumor Assays
D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel