Role of Autocrine Erythropoietin Signaling in the Survival of Human Breast Cancer Under Hypoxic Conditions

摘要

Erythropoietin(EPO) is induced by hypoxia and stimulates the proliferation and inhibits the apoptosis of Epo receptor (EpoR) bearing erythroblasts in the bone marrow. Hypoxia in human cancer is associated with invasion, metastasis, resistance to therapy. We have recently shown hypoxia- stimulated expression of Epo and EpoR in human breast cancer cell lines, suggesting a role for Epo signaling in breast cancer biology. We hypothesized that hypoxia induces increased expression of Epo and EpoR in breast cancers, and the increased Epo signaling results in inhibition of tumor cell apoptosis. Our aim during the second year of the proposed study was to determine the spatial distribution and correlation of tissue hypoxia as determined by EF5 binding with those of HIF-1alpha, Epo,EpoR and apoptotic activity in vivo in MCF-7 human breast cancer xenografts. We determined the intra- and interturmoral heterogeneity of apoptotic activity in the tumor. We have shown that tumor regions showing hypoxia are associated with significantly increase apoptotic activity. These regions also show increased Epo expression, and somewhat increased expression of the anti-apoptotic proteins bcl-2 and bcl-X1, consistent with their induction by Epo signaling. Our results suggest, that similar to our in vitro finding, tissue hypoxia in breast cancers induces increased apoptosis. At the same time, it also induces increased Epo expression in the tumors, likely leading to increased expression of anti-apoptotic proteins and protection of tumor cells from apoptotic death.