Abstract 1323: Lack of cyclin D3 enhances the CDK6-dependent skin tumor susceptibility to malignant progression

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The Cyclin-Dependent Kinases (CDKs) are a family of essential serine-threonine kinases that are cell cycle regulated by association with cyclins at specific time-points of the cell cycle. Specifically, D-type cyclins form complexes and activate CDK6 and CDK4. We have previously established that transgenic expression of CDK6 in mouse epidermis (K5CDK6 mice) alter an early stage of tumorigenesis leading to strong reduction of the multiplicity and incidence of skin tumors. Our previous results have shown that CDK6 preferentially binds to cyclin D3, which overexpression also decreases tumor development in mouse epidermis. Thus, we hypothesized that the association of CDK6/cyclin D3 and its enzymatic activity negatively impacts tumor development. To test this idea, we developed K5CDK6/Cyclin D3-/- mutant mice and subjected them to the two-stage carcinogenesis protocol. Contrary to our hypothesis, lack of cyclin D3 expression does not affect the tumor repression activity of CDK6 since both, K5CDK6 and K5CDK6/cyclin D3-/- mice, exhibit a severe reduction in the multiplicity and incidence of skin tumors compared to wild-type siblings. However, histopathological analysis of skin tumors revealed that 60% of the skin tumors in K5CDK6/cyclin D3-/- mice were classified as squamous-cell carcinomas I (SCC) with a variable degree of squamous differentiation; whereas wild type, K5CDK6 and cyclin D3-/- siblings exhibit benign tumors with no significant changes in the rate of malignant progression. Consistent with the malignant nature of the K5CDK6/cyclin D3-/- tumors, lack or reduction of cyclin D3 levels within the context of CDK6 overexpression (K5CDK6/D3-/- and K5CDK6/cyclin D3+/-) lead to 7-fold increase in tumor size compared to K5CDK6, cyclin D3-/- and wild-type tumors. Biochemical analysis of epidermal tumors shows that cyclin D3 ablation results in a rise of cyclin D1 protein levels. These data suggest that though cyclin D3 expression does not alter the tumor suppressive role of CDK6 at early stages of tumorigenesis, it does affect the expression of cyclin D1 resulting in the increased rate of malignant progression. Consistent with these studies, we have shown that elevated activity of CDK4/cyclin D1 complex results in an elevated number of SCC. We conclude that CDK6 activity can prevent tumor formation during the initial stages of tumorigenesis in a cyclin D3-independent manner and likely Rb-independent as well (Kollman et al, 2013). However, variations in the expression of cyclin D3 affects cyclin D2 (Rojas et al, 2007) and/or cyclin D1 levels, directly altering the susceptibility of CDK6 expressing tumors to malignant conversion. Therefore, therapies directed to reduce D-type cyclins expression should be considered within the context of the expression level of CDK6 and CDK4 to define the potential effect in the malignant progression of skin tumors. Supported by NIH grant CA116328. Note: This abstract was not presented at the meeting. Citation Format: Sung Hyun Lee, Xian Wang, Marcelo L. Rodriguez-Puebla. Lack of cyclin D3 enhances the CDK6-dependent skin tumor susceptibility to malignant progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1323. doi:10.1158/1538-7445.AM2014-1323