CDK2 is required for LMW-cyclin E mediated murine mammary tumorigenesis.

Abstract Abstract #2007 Cyclin E is a regulatory protein with multiple functions that activates CDK2, controls centrosome duplication, and regulates histone gene transcription. Our previous studies have shown that the presence of Low-molecular-weight (LMW) forms of cyclin E correlates strongly with decreased survival in patients with breast cancer. Transgenic mice overexpressing LMW cyclin E had increased incidence of mammary tumors and distant metastasis when compared to full length cyclin E. The critical role of LMW cyclin E in mammary tumorigenesis may be the result of the ability of LMW cyclin E to bind and activate the cyclin-dependent kinase 2 (CDK2). To specifically test the importance of LMW cyclin E-associated CDK2 kinase activity in mammary tumorigenesis, we generated double and triple transgenic mice LMW cyclin E-T1;CDK2-/-, and LMW cyclin E-T1;p53+/-;CDK2-/-. We found that: (i) The development of the mammary glands proceeds relatively normally in these animals demonstrating that CDK2 kinase activity is largely dispensable for mammary gland development; (ii) These mice were resistant to breast cancers initiated by LMW cyclin E overexpression. Whereas LMW-cyclin E-T1 mice in CDK2+/- or CDK2+/+ background succumb to mammary tumors with mean latencies of 16 and 19.5 months respectively, their LMW cyclin E-T1; CDK2-/- littermates do not form mammary tumors up to 24 months (P=0.05 CDK2+/+ versus CDK2-/-; P=0.0252 CDK2+/- versus CDK2-/-; P=0.1457 CDK2+/+ versus CDK2+/-, Log rank test). Similarly, while MMTV-LMW cyclin E-T1/p53+/- transgenic mice in CDK2+/- or CDK2+/+ background succumb to mammary gland tumors between 7 and 13 months with 100% penetrance, their MMTV-LMW cyclin E-T1;p53+/-; CDK2-/- littermates are resistant to tumor formation (P<0.01 CDK2+/+ versus CDK2-/-; P=0.011 CDK2+/- versus CDK2-/-, P=0.5072 CDK2+/+ versus CDK2+/-, Log rank Test). In fact none of the CDK2-/- mice developed mammary tumors when crossed with cyclin E LMW transgenic mice. However, 2 out of the 12 MMTV-LMW cyclin E; p53+/-; CDK2-/- mice generated salivary gland tumors. Hence, these LMW cyclin E; p53+/-; CDK2-/- are susceptible to LMW cyclin E induced salivary tumors in the absence of CDK2. We concluded that CDK2 is critically required for LMW cyclin E induced mammary tumorigenesis and consequently, the loss of CDK2 renders CDK2-/- mice resistant to breast cancer induced by LMW cyclin E expression. In clear contrast to mammary epithelial cells, we found that in salivary gland cells LMW cyclin E continued to elicit malignant transformation even in the absence of CDK2. Our work suggests that due to the requirement of CDK2 for LMW-cyclin E mediated mammary tumorigeneis, these tumors are prime candidates for anti-CDK2 therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2007.