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The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse

R Hakem1, J L de la Pompa, C Sirard

  • 1Amgen Institute, Toronto, Ontario, Canada.

Cell
|June 28, 1996
PubMed

Insights

Mutations in the BRCA1 gene are linked to cancer. Homozygous Brca1 mutant mouse embryos fail to develop properly and die early in embryogenesis due to impaired cell proliferation.

Area of Science:

  • Developmental biology
  • Genetics
  • Cancer research

Background:

  • Mutations in the BRCA1 gene are linked to hereditary breast and ovarian cancers in humans.
  • Brca1+/- mice are viable and do not develop tumors by 11 months of age.

Purpose of the Study:

  • To investigate the embryonic lethality of homozygous Brca1 mutations.
  • To understand the cellular mechanisms underlying embryonic development defects in Brca1 mutants.

Main Methods:

  • Generation and analysis of homozygous Brca1(5-6) mutant mice.
  • In vivo and in vitro studies of embryonic development, including cell proliferation and apoptosis assays.
  • Analysis of gene expression, including cyclin E, mdm-2, and p21.

Main Results:

  • Homozygous Brca1(5-6) mutant embryos exhibit developmental failure before day 7.5 of embryogenesis, with impaired mesoderm formation and abnormal extraembryonic development.
  • Mutant embryos show reduced cell proliferation and decreased expression of cyclin E and mdm-2, alongside a dramatic increase in p21 expression.
  • In vitro studies confirmed grossly impaired blastocyst growth in mutant embryos.

Conclusions:

  • Embryonic lethality of Brca1(5-6) mutant mice prior to gastrulation is likely caused by a failure in the proliferative burst essential for germ layer development.
  • BRCA1 plays a critical role in early embryonic cell proliferation and development, independent of its role in DNA repair related to cancer predisposition.

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