Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma.
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.
Schaffer
Bethany E
BE
Department of Pediatrics, Stanford Medical School, Stanford, California 94305-5149, USA.
Park
Kwon-Sik
KS
Yiu
Gloria
G
Conklin
Jamie F
JF
Lin
Chenwei
C
Burkhart
Deborah L
DL
Karnezis
Anthony N
AN
Sweet-Cordero
E Alejandro
EA
Sage
Julien
J
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*
D014408:Biomarkers, Tumor; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases
Clin Cancer Res. 2002 Dec;8(12):3850-6
12473599
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13790-5
11707567
J Exp Clin Cancer Res. 2008 Sep 15;27:38
18793406
Cancer Res. 2009 Nov 15;69(22):8733-41
19887614
Oncogene. 2005 Sep 1;24(38):5821-6
16044156
Cell. 2008 Mar 7;132(5):875-86
18329372
Cold Spring Harb Symp Quant Biol. 2005;70:225-32
16869758
Genome Biol. 2002 Aug 28;3(9):reviews3012
12225593
Cancer Cell. 2003 Sep;4(3):181-9
14522252
Semin Oncol. 2001 Apr;28(2 Suppl 4):3-13
11479891
J Natl Compr Canc Netw. 2008 Mar;6(3):315-22
18377849
Genes Dev. 2004 Dec 1;18(23):2952-62
15574596
Oncogene. 2009 Jan 29;28(4):500-8
18997819
Oncogene. 2009 Mar 12;28(10):1393-9
19151761
World J Surg Oncol. 2004 May 05;2:10
15128454
J Transl Med. 2008 Nov 07;6:69
18992152
Dev Biol. 2007 Oct 15;310(2):442-53
17765889
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13784-9
11707590
Cell Div. 2008 May 19;3:9
18489754
Cell Stem Cell. 2008 Oct 9;3(4):416-28
18940733
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6933-8
9192669