Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice

Cancer Res. 2007 Jul 15;67(14):6605-11. doi: 10.1158/0008-5472.CAN-06-4815.

Abstract

CDC25A phosphatase activates multiple cyclin-dependent kinases (CDK) during cell cycle progression. Inactivation of CDC25A by ubiquitin-mediated degradation is a major mechanism of DNA damage-induced S-G(2) checkpoint. Although increased CDC25A expression has been reported in various human cancer tissues, it remains unclear whether CDC25A activation is a critical rate-limiting step of carcinogenesis. To assess the role for CDC25A in cell cycle control and carcinogenesis, we used a Cdc25A-null mouse strain we recently generated. Whereas Cdc25A(-/-) mice exhibit early embryonic lethality, Cdc25A(+/-) mice show no appreciable developmental defect. Cdc25A(+/-) mouse embryonic fibroblasts (MEF) exhibit normal kinetics of cell cycle progression at early passages, modestly enhanced G(2) checkpoint response to DNA damage, and shortened proliferative life span, compared with wild-type MEFs. Importantly, Cdc25A(+/-) MEFs are significantly resistant to malignant transformation induced by coexpression of H-ras(V12) and a dominant negative p53 mutant. The rate-limiting role for CDC25A in transformation is further supported by decreased transformation efficiency in MCF-10A human mammary epithelial cells stably expressing CDC25A small interfering RNA. Consistently, Cdc25A(+/-) mice show substantially prolonged latency in mammary tumorigenesis induced by MMTV-H-ras or MMTV-neu transgene, whereas MMTV-myc-induced tumorigenesis is not significantly affected by Cdc25A heterozygosity. Mammary tissues of Cdc25A(+/-);MMTV-neu mice before tumor development display less proliferative response to the oncogene with increased tyrosine phosphorylation of CDK1/2, but show no significant change in apoptosis. These results suggest that Cdc25A plays a rate-limiting role in transformation and tumor initiation mediated by ras activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Fibroblasts / metabolism
  • G2 Phase
  • Gene Expression Regulation, Neoplastic*
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • S Phase
  • Time Factors
  • cdc25 Phosphatases / genetics*
  • cdc25 Phosphatases / physiology*
  • ras Proteins / metabolism*

Substances

  • CDC25A protein, human
  • Cdc25a protein, mouse
  • cdc25 Phosphatases
  • ras Proteins