Abstract
Here, we describe the surprising residual capability of the Rb pathway to negatively regulate proliferation and tumorigenesis in a SV40 large T antigen (Tag)-driven mouse model of pancreatic islet carcinogenesis. Heterogeneous Tag expression during all progression stages suggested that a threshold level of the T antigen oncoprotein might be deterministic for β-cell hyperproliferation and led us to hypothesize that Tag might not be fully inhibiting the tumor suppressor activity of Rb. Moreover, genomic profiling of these tumors by array CGH pointed to regions of loss on chromosomes 6 and 14, where the Rb pathway inhibitor p27 and Rb itself, respectively, reside. Indeed, genetic ablation of the p27Kip1 or Rb genes accentuated Tag-induced tumorigenesis, with loss of Rb in particular broadly enhancing multiple parameters of tumorigenesis including the frequency and growth rates of premalignant lesions, of nascent solid tumors, and of invasive carcinomas. The data indicate that attenuation rather than complete inactivation of Rb tumor suppressor gene function, in the context of p53 inhibition, is sufficient to initiate tumorigenesis in this model of islet cell cancer, with the demonstrable possibility that subsequent losses of Rb or its regulators can enhance malignant progression. The results may be relevant to human papillomavirus (HPV)-induced cervical neoplasias where E7 oncogene expression levels or activity (in the case of intermediate/low-risk HPV subtypes) incompletely inhibits Rb tumor suppressor functions, as well as to other neoplasias where initiating oncogenic or tumor suppressor events reduce but do not abrogate Rb function.
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Acknowledgements
We wish to thank Mark Magnuson (Vanderbilt University, Nashville, TN, USA) for providing us the RIP2-Cre transgenic mice and Anton Berns (The Netherlands Cancer Institute, Amsterdam, The Netherlands) for the Rb-floxed allele animals, and Cherry Concengo, Marina Vayner, Susan Cacacho and Ehud Drori for excellent technical support. This research was supported by grants from the US National Cancer Institute. DH is an American Cancer Society Research Professor, and thanks the ACS for their support.
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Casanovas, O., Hager, J., Chun, M. et al. Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene 24, 6597–6604 (2005). https://doi.org/10.1038/sj.onc.1208823
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DOI: https://doi.org/10.1038/sj.onc.1208823
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