Inhibition of protein geranylgeranylation requires p27^kip1 to induce human breast cancer cell death

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Decreased levels of the CDK inhibitor p27^Kip1 are associated with poor prognosis in breast cancer patients. We designed a novel tetrapeptide mimic inhibitor of geranylgeranyltransferase I (GGTase I), GGTI-2418, that significantly induces breast tumor cell death by increasing the protein levels of p27^Kip1. GGTI-2418, inhibits GGTase I competitively (Ki = 4.4 ± 1.6nM) and selectively (5600 fold) over farnesyltransferase. In human breast cancer cell lines, GGTI-2417 a methyl ester prodrug of GGTI-2418 induces p27^Kip1 levels, tumor cell death and G₀/G₁ accumulation. p27^Kip1 knockout cells and p27kip1 siRNA experiments demonstrated that GGTI-2417-induced breast tumor cell death requires p27^Kip1. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. In transgenic mice where breast tumors are driven by the oncogene ErbB2, GGTI-2418 induces significant tumor regression.