title: Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice.
abstract: Despite being the most evolutionarily conserved of the mammalian caspases, little is understood about the cellular function of caspase-2 in normal tissues or what role caspase-2 may have in the progression of human disease. It has been reported that deletion of the caspase-2 gene (Casp2), accelerates Eμ-myc lymphomagenesis in mice, and thus caspase-2 may act as a tumor suppressor in hematological malignancies. Here, we sought to extend these findings to epithelial cancers by examining the potential role of caspase-2 as a tumor suppressor in the mouse mammary carcinogenesis model; MMTV/c-neu. The rate of tumor acquisition was significantly higher in multiparous Casp2(-/-)/MMTV mice compared with Casp2(+/+)/MMTV and Casp2(+/-)/MMTV mice. Cells from Casp2(-/-)/MMTV tumors were often multinucleated and displayed bizarre mitoses and karyomegaly, while cells from Casp2(+/+)/MMTV and Casp2(+/-)/MMTV tumors never displayed this phenotype. Tumors from Casp2(-/-)/MMTV animals had a significantly higher mitotic index than tumors from Casp2(+/+)/MMTV and Casp2(+/-)/MMTV animals. Cell cycle analysis of Casp2(-/-) E1A/Ras-transformed mouse embryonic fibroblasts (MEF) also indicated a higher proliferative rate in the absence of caspase-2. In vitro assays further illustrated that MEF had increased genomic instability in the absence of caspase-2. This appears to be due to disruption of the p53 pathway because we observed a concomitant decrease in the induction of the p53 target genes, Pidd, p21 and Mdm2. Thus caspase-2 may function as a tumor suppressor, in part, through regulation of cell division and genomic stability.
authors: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: M J
authors: MJ
authors: Parsons
authors: L
authors: L
authors: McCormick
authors: L
authors: L
authors: Janke
authors: A
authors: A
authors: Howard
authors: L
authors: L
authors: Bouchier-Hayes
authors: D R
authors: DR
authors: Green
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C414729:Pidd1 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D053143:Caspase 2; D020741:rho GTP-Binding Proteins
references: Mol Cell. 2011 Jul 8;43(1):57-71
references: 21726810
references: EMBO J. 2009 Oct 21;28(20):3216-27
references: 19730412
references: Dev Cell. 2009 Jun;16(6):856-66
references: 19531356
references: Nature. 2010 Aug 12;466(7308):869-73
references: 20668451
references: Cancer Res. 2007 Jan 1;67(1):167-77
references: 17210696
references: Cell. 2008 May 30;133(5):864-77
references: 18510930
references: Cell Death Differ. 2012 Jan;19(1):51-7
references: 22075987
references: Cancer Res. 1998 Jun 15;58(12):2675-9
references: 9635596
references: Cell Death Differ. 2012 Aug;19(8):1288-98
references: 22498700
references: J Biol Chem. 1979 Sep 10;254(17):8679-89
references: 381311
references: Nat Genet. 2007 Apr;39(4):457-66
references: 17334365
references: Genes Dev. 1996 Apr 15;10(8):934-47
references: 8608941
references: Blood. 2005 Sep 1;106(5):1817-23
references: 15899912
references: Cell Oncol. 2010;32(1-2):29-42
references: 20208132
references: Expert Rev Mol Diagn. 2009 Jul;9(5):423-40
references: 19580428
references: Cancer Lett. 2003 Apr 10;193(1):49-55
references: 12691823
references: Clin Cancer Res. 2005 Oct 15;11(20):7226-33
references: 16243792
references: Genes Dev. 1998 May 1;12(9):1304-14
references: 9573047
references: Nat Cell Biol. 2006 Jan;8(1):72-7
references: 16362053
references: Cancer Res. 2009 Aug 1;69(15):6315-21
references: 19638575
references: Cell. 1992 Sep 18;70(6):923-35
references: 1356076
references: Cell. 1988 Jul 1;54(1):105-15
references: 2898299
references: Development. 1992 May;115(1):49-58
references: 1638991
references: APMIS. 2004 Jun;112(6):330-5
references: 15511269
references: J Neurosci. 2000 Feb 15;20(4):1386-92
references: 10662829
references: Leuk Lymphoma. 2001 Feb;40(5-6):471-81
references: 11426520
references: Blood. 1998 Nov 1;92(9):3090-7
references: 9787143
references: Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5336-41
references: 19279217
references: Cell. 1992 Sep 18;70(6):937-48
references: 1525830
references: Oncogene. 2008 May 29;27(24):3393-404
references: 18193089
references: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1816-21
references: 9050862
references: Cell Death Differ. 2012 Oct;19(10):1722-32
references: 22595758
references: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20489-93
references: 21059955
references: Nature. 2007 Nov 29;450(7170):721-4
references: 18046411
references: J Neurosci. 1998 Nov 15;18(22):9204-15
references: 9801360
references: Genome Biol. 2007;8(5):R76
references: 17493263
references: N Engl J Med. 1999 Jan 14;340(2):152-3; author reply 153-4
references: 9917220