Functional Significance of Erythropoietin Receptor Expression in Breast Cancer

Abstract

SUMMARY: Erythropoietin (EPO) is the principal hematopoietic cytokine that regulates mammalian erythropoiesis by binding to its transmembrane receptor EpoR. Recent experimental evidence suggests that the biologic effects of EPO are not limited to the regulation of erythropoiesis. In studies focusing on nonhematopoietic effects of EpoR signaling, we found high levels of EpoR protein expression in human breast cancer cells. The purpose of the present study was to evaluate clinical breast cancer specimens for EPO and EpoR expression, characterize the relationship between EPO expression and tumor hypoxia in biopsies prelabeled with hypoxia marker pimonidazole, analyze breast cancer cell lines for EpoR expression, and study the functional significance of EpoR expression in breast cancer cells in vivo. Immunohistochemical analysis for EPO, EpoR expression, and pimonidazole adducts was performed on 26 tumor biopsies with contiguous sections from 10 patients with breast cancer. High levels of EpoR expression were found in cancer cells in 90% of tumors. EPO expression was found in 60% of tumors and EPO and EpoR colocalization in tumor cells was present in many cases. The expression pattern of EPO with respect to tumor hypoxia was variable, without consistent colocalization of EPO and hypoxia in tumor cells. Human and rat breast cancer tissue culture cells express EpoR mRNA and protein. To study the in vivo function of EpoR expression in breast cancer cells, we used rat syngeneic R3230Ac mammary adenocarcinoma cells in a tumor Z-chamber model (dual porous plexiglass chambers containing fibrin gel, cancer cells, and a putative anti-tumor compound implanted into the subcutaneous tissue of rats). Local, one-time administration of a neutralizing anti-EPO antibody, soluble EPO receptor, or an inhibitor of Jak2, a cytoplasmic tyrosine kinase essential for EPO-mediated mitogenesis, resulted in a delay in tumor growth with 45% reduction in maximal tumor depth in tumor Z-chambers in a dose-dependent manner. These studies demonstrate the expression of functional receptors for EPO in breast cancer cells. (Lab Invest 2002, 82:911-918).

Erythropoietin and erythropoietin receptor expression in human prostate cancer

“…[18][19][20]24,[55][56][57][58][59][60][61][62] In experimental animal models of cancer, disruption of erythropoietin-erythropoietin receptor signaling in tumors was associated with an antitumor effect in xenografts of human female genital tract cancers and melanoma 58,61 and in a rodent syngeneic model of breast cancer. 19 The pathophysiologic role, if any, of erythropoietin receptor and erythropoietin coexpression in prostate cancer cells and whether exogenous recombinant erythropoietin may exert direct in vivo effects on tumor cells that express erythropoietin receptor remain to be determined. Our studies have shown the expression of erythropoietin receptor in monolayer cultures of hormonesensitive (LNCaP) and hormone-refractory (PC-3) cancer cell lines derived from human prostate cancer.…”

“…A predominantly cytoplasmic pattern of staining for both erythropoietin and erythropoietin receptor was present in cancer cells, consistent with the immunoreactivity pattern that we and others have observed in other types of neoplasms that express erythropoietin and erythropoietin receptor. 18,19,24,25 Erythropoietin receptor also showed membrane immunoreactivity in some of the neoplastic and host cells. In most of the sections, the intensely erythropoietin receptor stained neoplastic glands could clearly be identified infiltrating into their weakly reactive non-neoplastic counterparts.…”

“…17 A series of recent reports have described the expression of erythropoietin receptor and erythropoietin in several different types of human cancer cells. [18][19][20] In the present study, our objective was to determine whether human prostate cancer cells express the erythropoietin receptor and its ligand erythropoietin. We examined clinical specimens of primary prostate cancer for expression of erythropoietin receptor and erythropoietin protein using immunohistochemistry.…”

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…It should be noted that alongside the beneficial effects of EPO, a concern that EPO treatment for anemia might adversely affect the prognosis in certain cases of solid tumor cancers (Aapro et al, 2008;Henke et al, 2006;Longmore, 2007) has been raised. In that respect although EPO-Rs were found in certain solid tumors (Acs et al, 2003;Arcasoy et al, 2002;Yasuda et al, 2003), their functionality is still controversial Jeong et al, 2008;Laugsch et al, 2008).…”

Erythropoietin inhibits apoptosis induced by photodynamic therapy in ovarian cancer cells

“…Among these are ovary and uterus (29,30), melanoma (31), renal carcinoma (32), and clinical specimens of breast cancer as well as monolayer cultures of tumor cell lines derived from breast cancer (33,34), prostate cancer (20), and ovarian cancer (27,28). Using RT-PCR, Arcasoy et al (35) isolated and characterized several cDNAs for EpoR splice variants expressed in human cancer cells, which may modulate the reported cellular effects of recombinant human erythropoietin and erythropoietinEpoR antagonists.…”