Breast cancer cell migration and invasion: differential effects of raloxifene vs estrogens.

M. FLAMINI; A.M. SANCHEZ; S. GARIBALDI; C. BALDACCI; M.S. GIRETTI; P. MANNELLA; A. CARUSO; L. FORNARI; X.D. FU; 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

Selective oestrogen receptor modulators (SERMs) are largely considered in the treatment of breast cancer and osteoporosis. Raloxifene (Ral) is one those and it has been approved for prevention as well as treatment of postmenopausal osteoporosis. Indeed, Ral has been demonstrated to reduce risk of breast cancer. However, few is known about effects of Ral on breast cancer cell metastasis, which is the main cause of death. The aim of present study is to observe and compare the effects of Ral and estradiol (E2) plus Ral on T-47-D cells migration and invasion. Our findings show that Ral induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like membrane ruffles, pseudopodia, lamellipodia which represent the initial step for cell migration and invasion. This action depends on the rapid activation of moesin, the actin-regulatory protein of ERM family. In the presence of Ral, estrogen receptor interacts with the cell membrane G protein and sequentially recruits and activates small GTPase RhoA and its downstream kinase effector ROCK, leading to moesin activation. Cell migration and invasion assays demonstrate that both Ral and E2 promote cell migration and invasion in threedimensional matrix. Intriguingly, when the two drugs are given simultaneously, raloxifene shows an inhibitory effect on estrogen-promoted cell migration and invasion. Hence, Ral acts as ER antagonist in the process of breast cancer metastasis. These data have relevant clinical implications in postmenopausal women or in patients with breast cancer to alter the effects of estrogens on breast cancer cell metastasis.