Μελέτη της έκφρασης της ερυθροποιητίνης και των υποδοχέων της στον καρκίνο του μαστού. Συσχέτιση με άλλους βιολογικούς παράγοντες: ανοσοϊστοχημική μελέτη σε ιστολογικά παρασκευάσματα ασθενών και βιολογική-μοριακή ανάλυση σε κυτταρικές σειρές

Abstract

Erythropoietin (EPO) is a pleiotropic cytokine, acting on cell survival, proliferation, differentiation and angiogenesis. In addition to EPO’s endocrine properties, recently its autocrine/paracrine effects have been identified in a number of normal and neoplastic tissues, including breast cancer. Emerging clinical data question the safety of recombinant EPO administration for the treatment of cancer-related anemia, in breast cancer patients. Nevertheless, the biological significance and the regulation of EPO and its cognitive receptors (EPOR) expression in breast cancer remain mainly controversial. In the present study we examined EPO/EPOR system expression and regulation, in tissue specimens and breast cancer cell models. In order to clarify its biological significance and possible prognostic/predictive value, we have correlated its expression with clinicopathological data and biological characteristics of breast neoplasia,. Moreover, we assayed EPOR functionality and possible mechanisms of action, in an attempt to clarify the role of endogenous or recombinant EPO in breast cancer biology. Our findings suggest that EPO/EPOR expression follows breast cancer evolution and is strongly associated with promotion and selection of resistant and aggressive phenotype. Despite negative correlation with patient survival (overall and disease free), EPO andEPOR are not independent prognostic markers, as their expression strongly correlates with other established prognostic/predictive biological markers. We have revealed EPOR functionality in breast cancer cell models, using low doses of recombinant EPO, compatible with those used in clinical practice: EPO triggers multiple signaling pathways mediating antiapoptotic effects, actin cytoskeleton rearrangements, enhancing invasive/migratory potency and transcriptional modifications. In addition, we report an interaction with membrane initiated steroid (androgen, estrogen) signaling, a mechanism recognized as a promoter of endocrine resistance, potentiating the biological effects of EPO and regulating EPOR gene transcription. EPO’s interrelation with Tumor Necrosis Family (TNF) members (BAFF, APRIL, TWEAK) and their cognitive receptors, reflects the flexibility and the broadness of EPO/EPOR system in breast cancer biology, integrating inflammatory cytokines in regulating breast cancer cellular homeostasis, survivsal, differentiation and proliferation. Leading ultimately to modulation of the biological behavior of tumors. These actions relate on the concentration, time and duration of action, the cell type involved and the intracellular signaling cascade activated by the agent. Our findings suggest the multifaceted role of EPO in cell fate regulation and its possible involvement in breast cancer promotion. These properties could be of relevant therapeutic value, in view of tailored therapies in breast cancer, or other pathologies