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J. Biol. Chem., Vol. 278, Issue 26, 23441-23450, June 27, 2003

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The Role of Cyclin-dependent Kinase Inhibitor p27^Kip1 in Anti-HER2 Antibody-induced G₁ Cell Cycle Arrest and Tumor Growth Inhibition^*

Xiao-Feng Le , Francois-Xavier Claret , Amy Lammayot , Ling Tian , Deepa Deshpande , Ruth LaPushin , Ana M. Tari ¶ and Robert C. Bast, Jr.  ||

From the Departments of Experimental Therapeutics, Molecular Therapeutics, and ^¶Bioimmunnotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Cyclin-dependent kinase (CDK) inhibitor p27^Kip1 binds to the cyclin E·CDK2 complex and plays a major role in controlling cell cycle and cell growth. Our group and others have reported that anti-HER2 monoclonal antibodies exert inhibitory effects on HER2-overexpressing breast cancers through G₁ cell cycle arrest associated with induction of p27^Kip1 and reduction of CDK2. The role of p27^Kip1 in anti-HER2 antibody-induced cell cycle arrest and growth inhibition is, however, still uncertain. Here we have provided several lines of evidence supporting a critical role for p27^Kip1 in the anti-HER2 antibody-induced G₁ cell cycle arrest and tumor growth inhibition. Induction of p27^Kip1 and G₁ growth arrest by anti-HER2 antibody, murine 4D5, or humanized trastuzumab (Herceptin®) are concentration-dependent, time-dependent, irreversible, and long-lasting. The magnitude of G₁ cell cycle arrest induced by trastuzumab or 4D5 is well correlated with the level of p27^Kip1 protein induced. Up-regulation of p27^Kip1 and G₁ growth arrest could no longer be removed with as little as 14 h of treatment with trastuzumab. Anti-HER2 antibody-induced p27^Kip1 protein, G₁ arrest, and growth inhibition persist at least 5 days after a single treatment. The magnitude of growth inhibition of breast cancer cells induced by anti-HER2 antibody closely parallels the level of p27^Kip1 induced. Induced expression of exogenous p27^Kip1 results in a p27^Kip1 level-dependent G₁ cell cycle arrest and growth inhibition similar to that obtained with anti-HER2 antibodies. Reducing p27^Kip1 expression using p27^Kip1 small interfering RNA blocks anti-HER2 antibody-induced p27^Kip1 up-regulation and G₁ arrest. Treatment with anti-HER2 antibody significantly increases the half-life of p27^Kip1 protein. Inhibition of ubiquitin-proteasome pathway, but not inhibition of calpain and caspase activities, up-regulates p27^Kip1 protein to a degree comparable with that obtained with anti-HER2 antibodies. We have further demonstrated that anti-HER2 antibody significantly decreases threonine phosphorylation of p27^Kip1 protein at position 187 (Thr-187) and increases serine phosphorylation of p27^Kip1 protein at position 10 (Ser-10). Expression of S10A and T187A mutant p27^Kip1 protein increases the fraction of cells in G₁ and reduces a further antibody-induced G₁ arrest. Consequently, p27^Kip1 plays an important role in the anti-HER2 antibody-induced G₁ cell cycle arrest and tumor growth inhibition through post-translational regulation. Regulation of the phosphorylation of p27^Kip1 protein is one of the post-translational mechanisms by which anti-HER2 antibody upregulates the protein.

Received for publication, January 27, 2003 , and in revised form, April 5, 2003.

^* This work was supported in part by NCI, National Institutes of Health Grant CA39930 (to R. C. B.), Grant IRG3721206 from the University of Texas M. D. Anderson Cancer Center (to X.-F. L.), NCI, National Institutes of Health Grant 1R01CA90853-01A1 (to F.-X. C.), and United States Department of the Army Grant DAMD 17-02-1-0459 (to A. M. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 355, Houston, TX 77030-4009. Tel.: 713-792-7743; Fax: 713-792-7864; E-mail: rbast{at}mdanderson.org.

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