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Differential Effects of p21^WAF1/CIP1 Deficiency on MMTV-ras and MMTV-myc Mammary Tumor Properties¹

Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724 [D. J. B.]; Departments of Developmental and Molecular Biology and Medicine, Division of Hormone-Dependent Tumor Biology, The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461 [R. J. L., R. G. P.]; Department of Pathology, The University of Texas Health Science Center at San Antonio, Texas 78229 [D. A. T.]; and Massey Cancer Center and Department of Human Genetics, Virginia Commonwealth University, Richmond, Virginia 23298 [J. J. W.]

p21^WAF1/CIP1 (p21) functions as a cyclin-dependent kinase (CDK) inhibitor and is a key mediator of p53-dependent growth arrest. However, its role in cell cycle regulation is complex, because it also appears to promote CDK activity in certain experimental contexts. Its potential role in tumor suppression was evaluated in MMTV-ras and MMTV-myc transgenic mice that were interbred to p21^WAF1/CIP1 knockout mice (p21^-/-). p21 deficiency had differential effects on tumor incidence and age of onset, proliferation, and apoptosis in the presence of these two oncogenes. Tumors arising in MMTV-ras/p21^-/- mice displayed higher S-phase fractions and correspondingly increased cyclin D1 and E/CDK activity than MMTV-ras tumors. In contrast, MMTV-myc/p21^-/- tumors had lower S-phase fractions and levels of cyclin D1 and E/CDK activity than MMTV-myc tumors. In both tumor types, changes in cyclin D1 and E/CDK activity were paralleled by changes in the corresponding cyclin protein levels. Tumor cell apoptosis was also differentially influenced by p21 deficiency in the two models. MMTV-ras/p21^-/- tumors exhibited a significant increase in spontaneous apoptosis as compared with MMTV-ras tumors, whereas p21 deficiency had minimal effect on apoptosis in MMTV-myc tumors. These results indicate that the effects of p21 expression on cellular proliferation are differentially affected by the expression of different oncogenes, and that p21 may play a role in promoting either growth arrest or proliferation, depending on the specific cellular context.

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