title: Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma.
abstract: Small-cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. Although SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs. Emerging evidence in patients and mouse models suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development in this triple-knockout mouse model. The histopathologic features of the triple-mutant mouse tumors closely resembled that of human SCLC. Genome-wide expression profiling experiments further showed that Rb/p53/p130-mutant mouse tumors were similar to human SCLC. These findings indicate that p130 plays a key tumor suppressor role in SCLC. Rb/p53/p130-mutant mice provide a novel preclinical mouse model to identify novel therapeutic targets against SCLC.
authors.affiliation: Department of Pediatrics, Stanford Medical School, Stanford, California 94305-5149, USA.
authors.forename: Bethany E
authors.initials: BE
authors.lastname: Schaffer
authors.forename: Kwon-Sik
authors.initials: KS
authors.lastname: Park
authors.forename: Gloria
authors.initials: G
authors.lastname: Yiu
authors.forename: Jamie F
authors.initials: JF
authors.lastname: Conklin
authors.forename: Chenwei
authors.initials: C
authors.lastname: Lin
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Burkhart
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130 / Q000502:physiology*; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases
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