EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

Abstract

The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα(+)) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

Erythropoietin and Cancer: The Unintended Consequences of Anemia Correction

“…Furthermore, EPOR receptor was shown to enhance ER activity and promote cell proliferation (58). Several correlations between EPOR, ER, and other steroid receptors expression have been described (54, 55, 59, 60).…”

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

“…More controversially, rhEPO has been reported to negatively affect outcomes among patients receiving chemotherapy for certain cancers including breast, head/neck, and additional malignancies 15, 36-39 . The extent to which tumor cells express EPORs at meaningful densities is also controversial, but EPOR expression levels overall are quite low-level 40-42 , and with recent notable exceptions 40, 41, 43 most EPOR antibodies are not so sensitive or specific 40, 42 . In studies using an A82 EPOR antibody, EPOR expression in a human cancer cell line panel was nominal 44 .…”

“…In xenograft experiments for several human cancer cell lines no significant effects of rhEPO on tumor growth were observed 45 , and in a study of primary tumor cells from 186 patients, rhEPO did not significantly activate AKT or MAPK signaling 46 . Nonetheless, in recent studies using an antiserum to a hEPO C-terminal epitope, EPOR expression has been reported among breast cancer cell lines, and associated with estrogen receptor-alpha activation 43 . Via RNAi approaches, the EPOR furthermore has been indicated to modulate tumor cell growth, survival and/or migration in melanoma 47 , renal carcinoma 48 and breast cancer cell lines 43 .…”

“…Nonetheless, in recent studies using an antiserum to a hEPO C-terminal epitope, EPOR expression has been reported among breast cancer cell lines, and associated with estrogen receptor-alpha activation 43 . Via RNAi approaches, the EPOR furthermore has been indicated to modulate tumor cell growth, survival and/or migration in melanoma 47 , renal carcinoma 48 and breast cancer cell lines 43 .…”

Roles of microRNA-221/222 in type 2 diabetic patients with post-menopausal breast cancer

“…Studies have additionally shown that the conversion rate in obese people is higher than that in lean people. Estrogen level is positively correlated with body weight (Du et al, 2014;Reinbothe et al, 2014). After menopause, estrogen level gradually declines while body fat content increases.…”