Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis.
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 beta-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 p27(Kip1) 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.
Casanovas
Oriol
O
Department of Biochemistry and Biophysics, Diabetes Center and Comprehensive Cancer Center, University of California-San Francisco, 94143, USA.
Hager
Jeffrey H
JH
Chun
Matthew Gee Hong
MG
Hanahan
Douglas
D
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016161:Genes, Retinoblastoma; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27