Translational Aspects of Erythropoietin Receptor and Hypoxia-Inducible Factors in Breast Cancer

The main function of erythropoietin (EPO) is in hematopoiesis where EPO stimulates increased proliferation, survival and differentiation of erythrocytic precursors in response to hypoxia. The EPO effect is mediated via binding to the EPO receptor (EPOR), which induces activation of different intracellular signaling pathways. Recombinant human EPO (rhEPO) is also used in treatment of cancer patients with anemia but some studies have reported negative effects on patient survival. Here we demonstrate a correlation between increased Hb levels and tumor response in patients with metastatic breast cancer and anemia, treated with rhEPO. The improved tumor response seen in patients with increased Hb levels might be due to improved oxygenation in tumors counteracting negative effects of hypoxia.

EPOR has also been found in non-hematopoietic tissues and in tumors of various origins. We have evaluated EPOR expression in breast tumors from a clinical trial evaluating tamoxifen treatment versus no adjuvant treatment. We found that high EPOR expression correlates to impaired tamoxifen response in patients with estrogen receptor (ER) positive tumors. EPOR expression also correlated to survival in these patients. When further investigating EPOR function we found that EPOR knockdown impaired proliferation in ER positive, but not ER negative breast cancer cells, supposedly via modulating effects of ER activity. EPOR knockdown also improved tamoxifen response in ER positive breast cancer cells. These effects were not dependent on EPO. Our results suggest an EPO-independent but ER-dependent function of EPOR in breast cancer cells.

Hypoxia is a common feature of solid tumors and is believed to be a consequence of tumors outgrowing their vasculature. Tumor hypoxia is associated with a more aggressive phenotype and treatment resistance. The main regulators of the hypoxic response are the hypoxia-inducible factors (HIFs) 1 & 2. We have investigated HIF-1α and HIF-2α expression in breast cancer and found a correlation between HIF-2α expression and distant metastasis and impaired prognosis, suggesting that HIF-2α has an important role in tumor progression. We also show differential time and oxygen dependent regulation of the two different HIF-α subunits and differences in their contribution to inducing VEGF expression.