Progesterone and medroxyprogesterone acetate induce T47-D breast cancer cell migration and invasion via differential signal transduction pathway.

X.D. FU; M.S. GIRETTI; A.M. SANCHEZ; P. MANNELLA; S. GARIBALDI; C. BALDACCI; M. FLAMINI; A. CARUSO; S. BEGLIUOMINI; S. PISANESCHI; A.R. GENAZZANI; T. SIMONCINI

8-11 March, Rome, Italy

Congreso; The 2nd World Congress on Gender-Specific Medicine and Ageing. The Endocrine Impact.; 2007

Metastases in breast cancer patients are the main cause of death. Cell migration and invasion are critical steps in the progress of tumor metastasis. Recently we have shown that in T47D breast cancer cells both progesterone (P) and medroxyprogesterone acetate (MPA) induce actin cytoskeleton remodeling and promote cell migration and invasion by rapid activation of moesin, a member of ezrin/radixin/moesin (ERM) family involved in cytoskeleton reorganization and maintenance of cell motility. However, the signal transduction pathways responsible for these events remain obscure. In this study, we show that in the presence of P, the progesterone receptor (PR) isoform A interacts with the G protein G13, leading to the activation of the small GTPase RhoA and of the downstream effector Rho-associated kinase (ROCK), which subsequently phosphorylates moesin on Thr 558. On the other hand, MPAPR binding leads to PR interaction with tyrosine kinase c-Src and activates RhoA/ROCK/moesin cascade via phosphotidininositol-3 kinase (PI3K)/Akt pathway. However, the inhibition of mitogen activated protein kinase (MAPK) with PD98059 reduces P-dependent cell migration while inhibition of PI3K/Akt with wortmannin impairs the effect of MPA. Cell invasion assay demonstrates that the two progestin promote the invasive ability. Intriguingly, the activation of MAPK and PI3K/Akt also partially plays the role in this process. In conclusion, our findings demonstrate that P and MPA enhance T47D breast cancer cell metastasis by activating moesin through divergent signal transduction pathways. These data will be beneficial to generate in the future the novel therapeutic tools to treat breast cancer metastases.