Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice

Cell Death Differ. 2013 Sep;20(9):1174-82. doi: 10.1038/cdd.2013.38. Epub 2013 May 3.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Caspase 2 / genetics
  • Caspase 2 / metabolism*
  • Cell Cycle / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cells, Cultured
  • Death Domain Receptor Signaling Adaptor Proteins / genetics
  • Female
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Tumor Virus, Mouse / genetics*
  • Mammary Tumor Virus, Mouse / metabolism
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism


  • Death Domain Receptor Signaling Adaptor Proteins
  • Pidd1 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Caspase 2
  • rho GTP-Binding Proteins