Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI‐277 on inhibition of MCF‐7 breast cancer cell‐cycle progression

Abstract

The efficacy of tamoxifen in the hormonal therapy of breast cancer is well established, but therapeutic resistance is inevitable. FTIs are a new class of anticancer drugs that are in phase III clinical evaluation. Since the mechanisms of action of these 2 classes of drugs are different, we tested the combination of tamoxifen and FTI-277 on inhibiting proliferation of hormone-dependent MCF-7 human breast cancer cells. An additive effect on cell proliferation was demonstrated, accompanied by an additive G(0)/G(1) arrest. The major effect of the combination of the 2 drugs was to maintain p21(waf/cip1) at an intermediate level, higher than that observed in the presence of tamoxifen alone. This was associated with an additive effect on inactivation of cyclin E-Cdk2 complexes and decreased phosphorylation of pRb and p130 pocket proteins. These effects were accompanied by increased association of 2 CDIs, p27(kip1) and p21(waf/cip1), with cyclin E-Cdk2 complexes. These data demonstrate that the additive effect is likely predominantly due to the recruitment of p27(kip1) and, to a lesser extent, p21(waf/cip1) into the cyclin E-Cdk2 complexes. Together, these results suggest that the combination of FTI and tamoxifen may increase the antitumor effect of either drug alone in breast cancer.