Tumor formation in Brca1 conditional mutant mice.
BRCA1 is the first breast cancer-associated gene, whose mutation predisposes women to breast and ovarian cancers. Targeted mutations of Brca1 in the mouse result in embryonic lethality primarily attributed to cellular proliferation defects, raising questions about the mechanisms by which Brca1 represses tumor formation. To overcome the early lethality, we engineered Brca1 by flanking its exon 11 with loxP sites. We showed that deletion of the exon by EIIA-Cre, which expresses Cre in the germline, causes p53-dependent lethality at late gestation. On the other hand, MMTV-Cre, which expresses Cre in mammary epithelium, resulted in tumorigenesis at low frequency after a long latency, accompanied by increased epithelial cell apoptosis and abnormal ductal development. Mammary tumor formation was significantly accelerated in a p53(+/-) genetic background; however, it still appeared in a stochastic fashion, suggesting the involvement of additional factors. Notably, the tumors were highly diverse in histopathology and displayed extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27, and Cyclin D1, and downregulation of p16 in the majority of tumors. This observation suggests roles for these proteins in Brca1-associated tumorigenesis.
Deng
Chu-Xia
CX
Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. chuxiad@bdg10.niddk.nih.gov
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53