Farnesyl
transferase inhibitors (FTIs) were shown to be effective in modulating
tumor growth in Ras-transformed
tumor cells. Recent studies have focused on
Rho GTPases as putative targets of FTI action. Previously, we demonstrated that FTIs were effective in inhibiting the growth and invasiveness of
RhoC GTPase-overexpressing
inflammatory breast cancer (IBC) cells however, RhoC activity was increased. In this study, we examine the mechanisms of FTI action on
breast cancer cells in culture through modulation of RhoC and RhoA
GTPases. We found that FTI inhibition of
breast cancer cell growth was reversible and resembled what has been described for an in vitro model of
tumor cell dormancy. On FTI treatment, levels of active RhoA decreased significantly, whereas levels of active RhoC increased 3.8-fold. We studied the role of these two
GTPases in a
fibronectin and basic FGF-induced model of
breast cancer cell dormancy. Hypoactivation of RhoA and hyperactivation of RhoC were seen to induce morphology and growth changes consistent with
tumor cell dormancy in culture. In addition, the JNK/SAPK pathway was induced on FTI treatment. A pharmacologic inhibitor of the JNK/SAPK pathway significantly reduced the number of dormant cells. This study has implications for the use of FTIs as therapeutic agents as well as potential mechanisms for
breast cancer cell dormancy.