Data from Cyclin D2–Cyclin-Dependent Kinase 4/6 Is Required for Efficient Proliferation and Tumorigenesis following Apc Loss

Abstract

Abstract Inactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in ApcMin/+ mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from ApcMin/+ mice. Taken together, these results indicate that cyclin D–CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC. Cancer Res; 70(20); 8149–58. ©2010 AACR.

Authors 11

1. Alicia M. Cole

   Cancer Research UK Scotland Institute

   Affiliation as printed

   Beatson Institute of Cancer Research, Glasgow, United Kingdom;

2. Kevin Myant

   Cancer Research UK Scotland Institute

   Affiliation as printed

   Beatson Institute of Cancer Research, Glasgow, United Kingdom;

3. Karen R. Reed

   Cardiff University

   Affiliation as printed

   School of Biosciences, Cardiff, United Kingdom;

4. Rachel A. Ridgway

   Cancer Research UK Scotland Institute

   Affiliation as printed

   Beatson Institute of Cancer Research, Glasgow, United Kingdom;

5. Dimitris Athineos

   Cancer Research UK Scotland Institute

   Affiliation as printed

   Beatson Institute of Cancer Research, Glasgow, United Kingdom;

6. Gijs R. VAN DEN BRINK Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Leiden, the Netherlands;

7. Vanesa Muncan Aachen

   Leiden University Medical Center

   Affiliation as printed

   Hubrecht Laboratorium, Utrecht, the Netherlands;

   Leiden University Medical Center, Leiden, the Netherlands;

8. Hans C. Clevers
   Affiliation as printed

   Hubrecht Laboratorium, Utrecht, the Netherlands;

9. Alan Richard Clarke

   Harvard University · Dana-Farber Cancer Institute

   Affiliation as printed

   Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts

10. Peter Sicinski

    Harvard University · Dana-Farber Cancer Institute

    Affiliation as printed

    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts

11. Owen James Sansom corresponding

    Cancer Research UK Scotland Institute

    Affiliation as printed

    Beatson Institute of Cancer Research, Glasgow, United Kingdom;