Retroviral transduction of splice variant Brca1-Delta11 or mutant Brca1-W1777Stop causes mouse epithelial mammary atypical duct hyperplasia.

摘要

We have investigated the effects of the expression of wild-type and mutant Brca1 alleles on the murine mammary gland morphogenesis and carcinogenesis. Primary cultures of mammary cells from BALB/cByJIco mice were infected with recombinant Babe Puro retroviruses expressing lacZ, full-length Brca1, splice variant Brca1-Delta11, or mutant Brca1-W1777Stop alleles. Infected cells were reinjected into the mammary fat pad of a syngeneic virgin mouse whose endogenous epithelium had previously been removed. Four months after reinjection, nulliparous and postlactating mice were checked for the reconstitution of the mammary gland. Stable expression of beta-galactosidase was observed in the ducts formed by epithelial mammary cells infected with Babe Puro/ lacZ retrovirus. Epithelial mammary cells transduced with full-length Brca1 developed normally, whereas those transduced with Brca1-Delta11 or Brca1-W1777Stop formed atypical duct hyperplasia associated with reduced branching. These results suggest that ectopically expressed splice variant Brca1-Delta11 and mutant Brca1-W1777Stop have dominant negative effects.