Characterizing a Rat Brca2 Knockout Model

摘要

Brca2 mutation carriers, while rare in the population have a high probability to develop breast cancer. In order to better understand the etiology of this disease as well as to develop prevention and treatment strategies for it we require good animal models. In this project we characterized the first rat knockout prnduced which was that of the Brca2 locus. We showed that Brca24-rats survive and develop multiple cancers but not breast cancer. The lack of breast cancer was likely due to a Brca2-/- associated lack of ovarian follicular development. We developed two approaches to address this problem using inbred WF rats on which this knockout allele was placed. The first involved trans-planting wild-type ovaries to knockout rats. Brca2-/- rats having wild type ovaries did not develop mammary carninomas due to regression of the transplanted tissue over time. The alternative strategy was to transplant mammary glands from Brca2-/- rats into wild type rats. Brca2- /- mammary glands did not develop carcinomas when transplanted into wild type recipients. However their morphologic characteristics differed from wild type transplants showing a higher degree of branching and lobularity. As an alternative to these transplant models we induced mammary carcinomas in Brca2+/- and Brca2+/+ controls with 7,12,dimethylbenz(a)anthracene (DMBA) and nitrosomethylurea (NMU), but found no differences in tumor multiplicity between the two genotypes. Although we were unable to produce a mammary tumor model the Brca2-/-knockout rat provides a valuable complement to existing mouse models to study the tissue-specific functions of the Brca2 protein.