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Established and new mouse models reveal E2f1 and Cdk2 dependency of retinoblastoma, and expose effective strategies to block tumor initiation

Oncogene volume 31, pages 5019–5028 (2012)Cite this article

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Abstract

RB+/− individuals develop retinoblastoma and, subsequently, many other tumors. The Rb relatives p107 and p130 protect the tumor-resistant Rb−/− mouse retina. Determining the mechanism underlying this tumor suppressor function may expose novel strategies to block Rb pathway cancers. p107/p130 are best known as E2f inhibitors, but here we implicate E2f-independent Cdk2 inhibition as the critical p107 tumor suppressor function in vivo. Like p107 loss, deleting p27 or inactivating its Cdk inhibitor (CKI) function (p27CK−) cooperated with Rb loss to induce retinoblastoma. Genetically, p107 behaved like a CKI because inactivating Rb and one allele each of p27 and p107 was tumorigenic. Although Rb loss induced canonical E2f targets, unexpectedly p107 loss did not further induce these genes, but instead caused post-transcriptional Skp2 induction and Cdk2 activation. Strikingly, Cdk2 activity correlated with tumor penetrance across all the retinoblastoma models. Therefore, Rb restrains E2f, but p107 inhibits cross talk to Cdk. While removing either E2f2 or E2f3 genes had little effect, removing only one E2f1 allele blocked tumorigenesis. More importantly, exposing retinoblastoma-prone fetuses to small molecule inhibitors of E2f (HLM006474) or Cdk (R547) for merely 1 week dramatically inhibited subsequent tumorigenesis in adult mice. Protection was achieved without disrupting normal proliferation. Thus, exquisite sensitivity of the cell-of-origin to E2f and Cdk activity can be exploited to prevent Rb pathway-induced cancer in vivo without perturbing normal cell division. These data suggest that E2f inhibitors, never before tested in vivo, or CKIs, largely disappointing as therapeutics, may be effective preventive agents.

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Acknowledgements

We thank Arnaud Besson and James Roberts for sharing p27CK–/CK– mice, and Fred Dick, Gustavo Leone and Philippe Monnier for comments. This project was funded by grants to RB from the Canadian Institutes for Health Research (CIHR), Foundation Fighting Blindness Canada, Ontario Institute for Cancer Research through funding provided by the Government of Ontario and the Terry Fox Research Institute. MS, MA and SRM were supported in part by fellowships from a CIHR training program.

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  1. Departments of Ophthalmology and Visual Science, Toronto Western Research Institute, University Health Network, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    M Sangwan, S R McCurdy, I Livne-bar, M Ahmad, D Chen & R Bremner

  2. Department of Molecular Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    J L Wrana

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  1. M Sangwan
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Correspondence to D Chen or R Bremner.

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Sangwan, M., McCurdy, S., Livne-bar, I. et al. Established and new mouse models reveal E2f1 and Cdk2 dependency of retinoblastoma, and expose effective strategies to block tumor initiation. Oncogene 31, 5019–5028 (2012). https://doi.org/10.1038/onc.2011.654

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