Retroviral transduction of splice variant Brca1-Δ11 or mutant Brca1-W1777Stop causes mouse epithelial mammary atypical duct hyperplasia

Abstract.

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-Δ11, 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 β-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-Δ11 or Brca1-W1777Stop formed atypical duct hyperplasia associated with reduced branching. These results suggest that ectopically expressed splice variant Brca1-Δ11 and mutant Brca1-W1777Stop have dominant negative effects.