The Tumor Suppressor Gene Brca1 Is Required for Embryonic Cellular Proliferation in the Mouse

Abstract

Mutations of the BRCA1 gone in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/- mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca1(5-6) mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca1(5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers.

Induction of apoptosis and G2/M cell cycle arrest by DCC

“…The result from heterozygous mice should be interpreted with caution. For example, heterozygous mice for BRCA1 or BRCA2 gene did not manifest defects or an increased rate of tumorigenesis (Liu et al, 1996;Hakem et al, 1996;Sharan et al, 1997). In addition, the phenotype of a tumor suppressor gene loss in human may not be mimicked by the phenotype in mice.…”

BRCA1 physically associates with p53 and stimulates its transcriptional activity

“…In our system using either the p21 or bax promoter, the combination of p53 and BRCA1 leads to more than an additive increase in gene expression, but it is not clear whether BRCA1 is required for p53-dependent transcription, because of the lack of availability of BRCA1-null cell lines. The BRCA1-knockout embryos appear to express p21 (Hakem et al, 1996) and the current model is that this may be due to genomic instability and subsequent p53 activation (Brugarolas and Jacks, 1997). The dominant negative action of truncated BRCA1 on p53-dependent transcription hints at the possibility that BRCA1 may be required for p53-dependent transcription.…”

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

“…Genes upregulated more than fivefold in the mammary glands of MMTV-Cre Brca1 Co/Co mice at day 1 of lactation include Cdkn1A (p21, up 16.3-fold), a cell cycle regulated that has previously been shown to be upregulated upon Brca1 repression (Hakem et al, 1996) and that has been implicated in breast cancer (Weiss, 2003); interferon-stimulated gene 15 (Isg15, up 10.9-fold) and the gene encoding the Isg15-interacting protein Ubp43 (up eightfold), the former being a ubiquitin-like gene implicated in immune response to viruses and in breast cancer (Bektas et al, 2008); oligoadenylate synthetase 1G (up 9.2-fold) and 1A (up 5.7-fold), an interferon-induced enzyme implicated in nucleotide metabolism and expressed in the mammary gland (Maia et al, 2008) and induced upon irradiation of human breast cancer cell lines (Tsai et al, 2007); and c-kit (up 5.58-fold), a hematopoietic stem cell marker that is overexpressed in undifferentiated mammary tumours (Tsuda et al, 2005) and functions as an oncogene in mammary epithelial cells (Tsuda et al, 2005;Raafat et al, 2007). Taken together, these genes suggest a role for Brca1 in the immune response and cancer.…”