Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol

Women who inherit mutations in the breast cancer susceptibility genes, BRCA 1 and BRCA2, are predisposed to the development of breast and ovarian cance r. We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALBl c(B1+/-) mice) or a Brca2 genetic alteration on the 129/SvEv genetic backgr ound (129(B2+/-) mice) to investigate potential gene-environment interactio ns between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES), Beginning at 3 weeks of age, BALB/c(B1+/ -), 129(B2+/-), and wild-type female mice were fed a control diet or a diet containing 640 ppb DES for 26 weeks. DES treatment caused vaginal epitheli al hyperplasia and hyperkeratosis, uterine inflammation, adenomyosis, and F ibrosis, as well as oviductal smooth muscle hypertrophy. The severity of th e DES response was mouse strain specific. The estrogen-responsive 129/SvEv strain exhibited an extreme response in the reproductive tract, whereas the effect in BALB/cJ and C3H/HeN(MMTV-) mice was less severe. The Brca1 and B rca2 genetic alterations influenced the phenotypic response of BALB/cJ and 129/SvEv inbred strains, respectively, to DES in the mammary gland and ovar y. The mammary duct branching morphology was inhibited in DES-treated BALB/ c(B1+/-) mice compared with similarly treated BALB/c(B1+/+) littermates. In addition, the majority of BALB/c(B1+/-) mice had atrophied ovaries, wherea s wild-type littermates were largely diagnosed with arrested follicular dev elopment, The mammary ductal architecture in untreated 129(B2+/-) mice reve aled a subtle inhibited branching phenotype that was enhanced with DES trea tment. However, no significant differences were observed in ovarian patholo gy between 129(B2+/+) and 129(B2+/-) mice. These data suggest that estrogen ic compounds may modulate mammary gland or ovarian morphology in BALB/c(B1/-) and 129(B2+/-) mice. These observations are consistent with the hypothe sis that compromised DNA repair processes in cells harboring Brca1 or Brca2 mutations lead to inhibited growth and differentiation compared with the p roliferative response of wild-type cells to DES treatment.