Suppression of mammary carcinoma growth in vitro and in vivo by inducible expression of the Cdk inhibitor p21

Mammary carcinomas that develop in C3(1)/SV40 T-antigen (TAg) transgenic mi ce have lost the p53-mediated induction of p21, leading to increased cellul ar proliferation and significant elevations of cyclins and Cdks. To test wh ether p21 could serve as a target for anticancer therapy for this mammary c ancer model, a retroviral delivery system for the inducible expression of p 21 was developed. We demonstrate that overexpression of p21 in C3(1)/TAg ma mmary tumor cells using the retroviral inducible p21 expression system resu lts in increased apoptosis, reduced cell proliferation in vitro and reduced tumor growth in vivo associated with reduced expression of cyclins D1 and E, and Cdks 2, 4, and 6. Reciprocal changes in the expression of p21 and p2 7(Kip1), another cell-cycle regulator, were also observed. Because reduced p21 expression occurs frequently in human breast cancer, restoration of the Cdk inhibitor p21 by gene therapy approaches may provide a method for inhi biting mammary tumor progression.