Growth hormone (GH) and insulin-like growth factor (IGF-I) play a role in breast cancer (BC) development. We previously demonstrated that GH protects the estrogen receptor (ER) positive BC-derived MCF7 cell line towards the cytotoxic effects of doxorubicin (D), independently of IGF-I. This issue may be important in ER negative BC cells, that are more aggressive and more likely to develop chemoresistance. The aim of our study is to evaluate whether GH may impact chemoresistance phenotype of ER negative BC-derived MDA-MB-231 cell line and investigate the possible mechanisms implicated in the protective action of GH towards the cytotoxic effects of D in both ER positive and ER negative BC-derived cell lines. We found that GH protects ER negative MDA-MB-231 cells from the cytotoxic effects of D and GH receptor antagonist Pegvisomant (Peg) reduces GH-induced DNA synthesis also in these cells. In both MDA-MB-231 and MCF7 cells GH does not revert D-induced G2/M accumulation, but significantly reduces basal and D-induced apoptosis, an effect blocked by Peg. Glutathione S-Transferase activity is not implicated in the protective effects of GH, while D-induced apoptosis depends on JNK activation. GH reduces both basal and D-stimulated JNK transcriptional activity and phosphorylation. In conclusion, in human BC cell lines GH directly promotes resistance to apoptosis induced by chemotherapic drugs independently of ER expression by modulating JNK, further broadening the concept that GH excess may hamper cytotoxic BC treatment. These findings support the hypothesis that blocking GHR may be viewed as a potential new therapeutic approach to overcome chemoresistance especially in ER negative BC.

Growth hormone receptor blockade inhibits growth hormone-induced chemoresistance by restoring cytotoxic-induced apoptosis in breast cancer cells independently of estrogen receptor expression

MINOIA, Mariella;GENTILIN, Erica;MOLE', Daniela;ROSSI, Martina;FILIERI, Carlo;TAGLIATI, Federico;AMBROSIO, Maria Rosaria;DEGLI UBERTI, Ettore;ZATELLI, Maria Chiara
2012

Abstract

Growth hormone (GH) and insulin-like growth factor (IGF-I) play a role in breast cancer (BC) development. We previously demonstrated that GH protects the estrogen receptor (ER) positive BC-derived MCF7 cell line towards the cytotoxic effects of doxorubicin (D), independently of IGF-I. This issue may be important in ER negative BC cells, that are more aggressive and more likely to develop chemoresistance. The aim of our study is to evaluate whether GH may impact chemoresistance phenotype of ER negative BC-derived MDA-MB-231 cell line and investigate the possible mechanisms implicated in the protective action of GH towards the cytotoxic effects of D in both ER positive and ER negative BC-derived cell lines. We found that GH protects ER negative MDA-MB-231 cells from the cytotoxic effects of D and GH receptor antagonist Pegvisomant (Peg) reduces GH-induced DNA synthesis also in these cells. In both MDA-MB-231 and MCF7 cells GH does not revert D-induced G2/M accumulation, but significantly reduces basal and D-induced apoptosis, an effect blocked by Peg. Glutathione S-Transferase activity is not implicated in the protective effects of GH, while D-induced apoptosis depends on JNK activation. GH reduces both basal and D-stimulated JNK transcriptional activity and phosphorylation. In conclusion, in human BC cell lines GH directly promotes resistance to apoptosis induced by chemotherapic drugs independently of ER expression by modulating JNK, further broadening the concept that GH excess may hamper cytotoxic BC treatment. These findings support the hypothesis that blocking GHR may be viewed as a potential new therapeutic approach to overcome chemoresistance especially in ER negative BC.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2276624
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact