Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl : protein transferase inhibitor

For Ras oncoproteins to transform mammalian cells, they must be posttransla tionally modified with a farnesyl group in a reaction catalyzed by the enzy me farnesyl:protein transferase (FPTase),Inhibitors of FPTase have therefor e been developed as potential anticancer agents. These compounds reverse ma ny of the malignant phenotypes of Ras-transformed cells in culture and inhi bit the growth of tumor xenografts in nude mice. Furthermore, the FPTase in hibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor viru s (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice. Alth ough these data support the further development of FTIs, it should be noted that Iii-ras is the ms gene most frequently mutated in human cancers. More over, Ki-RasB hinds more tightly to FPTase than either Ha- or N-Ras, and th us higher concentrations of FTIs that are competitive with the protein subs trate may be required to inhibit Ki-Ras processing. Given the unique bioche mical and biological features of Ki-RasB, it is important to evaluate the e fficacy of FTIs or any other modulator of oncogenic Ras function in model s ystems expressing this Ras oncoprotein. We have developed strains of transg enic mice carrying the human Ki-rasB cDNA with an activating mutation (G12V ) under the control of the MMTV enhancer/promoter. The predominant patholog ical feature that develops in these mice is the stochastic appearance of ma mmary adenocarcinomas. High levels of the Ki-rasB transgene RNA are detecte d in these tumors. Treatment of MMTV-Ki-rasB mice with L-744,832 caused inh ibition of tumor growth in the absence of systemic toxicity. Although FPTas e activity was inhibited in tumors from the treated mice, unprocessed Ki-Ra sB was not detected. These results demonstrate the utility of the MMTV-Ki-r asB transgenic mice for testing potential anticancer agents. Additionally, the data suggest that although the FTI L-744,832 can inhibit tumor gros-th in this model, Ki-Ras may not be the sole mediator of the biological effect s of the FTI.