Abstract 571: Overactive Cdk2 permits polyploidy by overwhelming the tetraploidy checkpoint.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The p53-dependent tetraploidy checkpoint serves to block the proliferation of cells that double their genome without dividing. Oftentimes, cancers will contain a tetraploid sub-population, indicating either an ability to bypass this checkpoint or that the checkpoint is no longer functional. In studying the chromosomal instability of tumor cell lines from mice with mammary expression of a constitutively active Cyclin D1-Cdk2 fusion protein (D1K2), we noticed an increased rate of polyploidization in the presence of the spindle-poison paclitaxel. This was recapitulated in an MCF10A cell line model, and it was discovered that this is due to the inability of the tetraploidy checkpoint to completely stop DNA replication in tetraploid cells with constitutively active Cdk2. Biochemical analysis shows that tetraploid cells expressing D1K2 maintain Rb phosphorylation longer than tetraploid control cells, matching the phenotype seen in cells that have p53 stably knocked down. Further DNA replication, yielding octaploid cells, appears to further intensify the tetraploidy checkpoint, arresting the cells. Due to the fact that approximately 50% of all breast cancers overexpress Cyclin D, these observations raise intriguing questions about the treatment of tumors with overactive Cdk2. While it appears these tetraploid MCF10A cells are unviable, we can not account for other mutations that may exist in vivo and allow the proliferation of a chromosomally unstable tetraploid tumor population. Citation Format: Stephan Jahn, Patrick Corsino, Mary Law, Brad Davis, Brian Law. Overactive Cdk2 permits polyploidy by overwhelming the tetraploidy checkpoint. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 571. doi:10.1158/1538-7445.AM2013-571