PT  - JOURNAL ARTICLE
AU  - Nadia Rucci
AU  - Irene Recchia
AU  - Adriano Angelucci
AU  - Marina Alamanou
AU  - Andrea Del Fattore
AU  - Dario Fortunati
AU  - Mira Šuša
AU  - Doriano Fabbro
AU  - Mauro Bologna
AU  - Anna Teti
TI  - Inhibition of Protein Kinase c-Src Reduces the Incidence of Breast Cancer Metastases and Increases Survival in Mice: Implications for Therapy
AID  - 10.1124/jpet.106.102004
DP  - 2006 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 161--172
VI  - 318
IP  - 1
4099  - http://jpet.aspetjournals.org/content/318/1/161.short
4100  - http://jpet.aspetjournals.org/content/318/1/161.full
SO  - J Pharmacol Exp Ther2006 Jul 01; 318
AB  - c-Src is a proto-oncogene, belonging to the nonreceptor protein kinases family, which plays a prominent role in carcinogenesis. In this study, we tested the hypothesis that c-Src could promote breast cancer metastasis acting on several cell types and that pharmacological disruption of its kinase activity could be beneficial for the treatment of metastases. Female BALB/c-nu/nu mice were subjected to intracardiac injection of the human breast cancer cells MDA-MB-231 (MDA-231), which induced prominent bone and visceral metastases. These were pharmacologically reduced by treatment with the c-Src inhibitor [7-{4-[2-(2-methoxy-ethylamino-ethoxy]-phenyl}-5-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine] CGP76030 (100 mg/kg/day p.o.), resulting in decreased morbidity and lethality. Metastases were more severe in mice injected with MDA-231 cells stably transfected with wild-type c-Src (MDA-231-SrcWT), whereas transfection in injected cells of a c-Src kinase-dead dominant-negative construct (MDA-231-SrcDN) resulted in reduced morbidity, lethality, and incidence of metastases similar to the mice treated with the inhibitor. An analogous beneficial effect of c-Src inhibition was observed in subcutaneous and intratibial implanted tumors. In vitro, c-Src suppression reduced MDA-231 cell aggressiveness. It also impaired osteoclast bone resorption both directly and by reducing expression by osteoblasts of the osteoclastogenic cytokines interleukin-1β and interleukin-6, whereas parathyroid hormone-related peptide was not implicated. c-Src was also modestly but consistently involved in the enhancement of endothelial cell proliferation in vitro and angiogenesis in vivo. In conclusion, we propose that c-Src disruption affects the metastatic process and thus is a therapeutic target for the treatment of breast cancer. The American Society for Pharmacology and Experimental Therapeutics