Erythropoietin Concomitantly with Ethinyl Estradiol can Cause Uterine and Ovarian Cancers

Erythropoietin (Epo), by binding to its receptor (EpoR), protects erythroid progenitor cells from apoptotic death and stimulates their proliferation and differentiation into hemoglobin-containing erythrocytes. In the body, the production of Epo in the kidney depends on the oxygen concentration in the circulating blood, i.e. Epo is induced by hypoxia. However, we found that Epo production is induced by estradiol (E2) more than by hypoxia in the mouse uterus [1] and that the human ovaries, uterus, and cervix can produce Epo through the expression of Epo mRNA with Epo-EpoR signaling [2]. Deprivation of Epo signaling destroyed the surgically resected specimens of ovarian, uterine and cervical cancers through anti-Epo antibody and soluble form of EpoR which can bind to Epo secreted from cancer cells in vivo in nude mice [3] and in vitro [4]. Twenty-four malignant human cell lines including leukemia cell lines examined expressed Epo and EpoR mRNAs with respective proteins, regardless of their origin, type, genetic characteristics, and biological properties. Furthermore, deprivation of Epo signaling in xenografts of stomach choriocarcinoma and melanoma cell lines using the EpoR antagonist, EMP9, led to the destruction of these xenografts [5]. Epo-EpoR signaling has been found in breast cancers [6,7], prostate cancers [8] and many other cancers [9].