Increased Levels of Erythropoietin in Nipple Aspirate Fluid and in Ductal Cells from Breast Cancer Patients
BACKGROUND Erythropoietin (Epo), induced by hypoxia, controls the survival, proliferation, and differentiation of Epo receptor (EpoR)-bearing erythroid progenitors and plays a role in the protection of neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, resistance to therapy, and selection for cells with diminished apoptotic potential. The authors recently demonstrated the basal and hypoxia-stimulated expression of Epo and EpoR in human breast carcinoma cell lines and in breast carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of mammary neoplasms. METHODS The authors characterized the expression of Epo and EpoR by immunohistochemistry in 184 invasive mammary carcinomas and 158 in situ mammary carcinomas and benign mammary epithelium. They analyzed the correlation of Epo and EpoR immunostaining with clinicopathologic tumor features and the patients' smoking history. RESULTS Benign mammary epithelial cells showed weak-to-moderate expression of Epo and EpoR. EpoR immunostaining was increased in carcinomas compared with benign epithelium both in nonsmokers and smokers, and Epo immunostaining was increased in carcinomas compared with benign epithelium in nonsmokers but not in smokers. Prominent Epo staining was seen in tumor cells adjacent to necrotic areas and at the infiltrating edge of tumors. EpoR staining, but not Epo staining, was significantly greater in tumors that showed high histologic grade, tumor necrosis, lymphovascular invasion, lymph node metastases, and loss of hormone receptor expression. CONCLUSIONS The current findings suggest that increased EpoR expression may play an important role in breast carcinogenesis. The induction of autocrine or paracrine Epo signaling may represent a novel mechanism by which hypoxia can promote breast carcinoma.