Endocrine Abstracts

GH and insulin-like growth factor 1 (IGF1) are known to promote breast carcinogenesis. Even if breast cancer (BC) incidence in not increased in female acromegalic patients, mortality is greater as compared to general population. In order to evaluate whether GH/IGF1 excess might influence BC response to therapy, accounting for the increased mortality, we evaluated the effects of GH and IGF1 on cell proliferation of a BC cell line, the MCF7 cells, in the presence of doxorubicine (D), frequently used in BC chemotherapy. We found that in serum-free conditions GH and IGF1 induce MCF7 cell growth and protect the cells from the cytotoxic effects of D. GH effects are direct and not mediated by IGF1, since they are apparent also in the presence of an IGF1 receptor blocking antibody and disappear in the presence of the GH antagonist pegvisomant. resistance to chemotherapic drugs may be due to MDR-1 gene expression, encoding for the P-glycoprotein, a transmembrane pump which detoxifies the intracellular compartment. However, RT-PCR for MDR1 and immunofluorescence for P-gp and failed to identify any induction of P-gp expression by GH. In order to verify whether other GH-induced gene transcription mechanisms were involved, we transfected MCF7 cells with a plasmid encoding for the luciferase gene under the control of the c-fos promoter. c-fos is an early response gene, classically induced by GH. We found that luciferase activity was induced by treatment with GH, an effect blocked by pegvisomant. Treatment with D did not modify basal luciferase activity, but blocked GH transcriptional activity. Moreover, GH treatment did not influence the cell cycle progression abnormalities induced by D. These data altogether indicate that GH can directly induce resistance to chemotherapic drugs with a mechanism that does not involve GH-induced early gene transcription not cell cycle progression and support the hypothesis that GH excess might hamper BC treatment, possibly resulting in an increased mortality.