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

M J Parsons1, L McCormick, L Janke

  • 1Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.

Cell Death and Differentiation
|May 7, 2013
PubMed

Insights

Caspase-2 (Casp2) acts as a tumor suppressor by maintaining genomic stability and regulating cell division. Its absence in mice accelerated epithelial cancer development and increased genomic instability, impacting the p53 pathway.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Caspase-2 (Casp2) is highly conserved but its cellular function and role in human disease remain unclear.
  • Previous studies suggest Casp2 acts as a tumor suppressor in hematological malignancies.
  • This study investigates Casp2's role in epithelial cancers.

Purpose of the Study:

  • To examine the role of caspase-2 (Casp2) as a tumor suppressor in epithelial cancers using a mouse mammary carcinogenesis model.
  • To determine if Casp2 deficiency impacts tumor development, cell cycle progression, and genomic stability.

Main Methods:

  • Utilized the MMTV/c-neu mouse model to study mammary carcinogenesis in Casp2(-/-), Casp2(+/-), and Casp2(+/+) mice.
  • Analyzed tumor characteristics, including multinucleation, abnormal mitoses, karyomegaly, and mitotic index.
  • Performed cell cycle analysis and in vitro assays on Casp2(-/-) E1A/Ras-transformed mouse embryonic fibroblasts (MEFs).

Main Results:

  • Casp2(-/-) mice exhibited a significantly higher rate of tumor acquisition compared to Casp2(+/+) and Casp2(+/-) mice.
  • Tumor cells from Casp2(-/-) mice displayed multinucleation, bizarre mitoses, karyomegaly, and a higher mitotic index.
  • Casp2 deficiency in MEFs led to increased proliferation, genomic instability, and reduced induction of p53 target genes (Pidd, p21, Mdm2).

Conclusions:

  • Caspase-2 (Casp2) functions as a tumor suppressor in epithelial cancers.
  • Casp2 plays a critical role in maintaining genomic stability and regulating cell division.
  • The tumor-suppressive function of Casp2 is partly mediated through its regulation of the p53 pathway.

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