Context: Growth hormone (GH) and insulin-like growth factor I (IGF-I) 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. Objective: evaluate whether GH/IGF-I excess might influence BC response to chemotherapy. Design: we evaluated GH and IGF-1 effects on cell proliferation of a BC cell line, the MCF7 cells, in the presence of doxorubicine (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved. Results: GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I, since they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist Pegvisomant (Peg). The expression of the MDR1 gene, involved in resistance to chemotherapic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Peg inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain. Conclusions: These data indicate that GH can directly induce resistance to chemotherapic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.
Growth hormone excess promotes breast cancer chemoresistance
ZATELLI, Maria Chiara;MINOIA, Mariella;MOLE', Daniela;TAGLIATI, Federico;MARGUTTI, Angelo;BONDANELLI, Marta;AMBROSIO, Maria Rosaria;DEGLI UBERTI, Ettore
2009
Abstract
Context: Growth hormone (GH) and insulin-like growth factor I (IGF-I) 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. Objective: evaluate whether GH/IGF-I excess might influence BC response to chemotherapy. Design: we evaluated GH and IGF-1 effects on cell proliferation of a BC cell line, the MCF7 cells, in the presence of doxorubicine (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved. Results: GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I, since they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist Pegvisomant (Peg). The expression of the MDR1 gene, involved in resistance to chemotherapic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Peg inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain. Conclusions: These data indicate that GH can directly induce resistance to chemotherapic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
