This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bennett, L. M. Articles by Wiseman, R. W. Search for Related Content PubMed PubMed Citation Articles by Bennett, L. M. Articles by Wiseman, R. W.

Mice Heterozygous for a Brca1 or Brca2 Mutation Display Distinct Mammary Gland and Ovarian Phenotypes in Response to Diethylstilbestrol¹

Laboratories of Molecular Carcinogenesis [L. M. B., K. A. M., J. M., T. W., N. K. C., R. W. W.] and Experimental Pathology [B. J. D.], NIH, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Pathco, Inc., Research Triangle Park, North Carolina 27709 [J. C. S.]; and University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 [L. C. G., B. H. K.]

Women who inherit mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are predisposed to the development of breast and ovarian cancer. We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALB/c^B1+/- mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129^B2+/- mice) to investigate potential gene-environment interactions 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 epithelial hyperplasia and hyperkeratosis, uterine inflammation, adenomyosis, and fibrosis, as well as oviductal smooth muscle hypertrophy. The severity of the 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 Brca2 genetic alterations influenced the phenotypic response of BALB/cJ and 129/SvEv inbred strains, respectively, to DES in the mammary gland and ovary. 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, whereas wild-type littermates were largely diagnosed with arrested follicular development. The mammary ductal architecture in untreated 129^B2+/- mice revealed a subtle inhibited branching phenotype that was enhanced with DES treatment. However, no significant differences were observed in ovarian pathology between 129^B2+/+ and 129^B2+/- mice. These data suggest that estrogenic compounds may modulate mammary gland or ovarian morphology in BALB/c^B1+/- and 129^B2+/- mice. These observations are consistent with the hypothesis that compromised DNA repair processes in cells harboring Brca1 or Brca2 mutations lead to inhibited growth and differentiation compared with the proliferative response of wild-type cells to DES treatment.

This article has been cited by other articles:

				T. A. King, W. Li, E. Brogi, C. J. Yee, M. L. Gemignani, N. Olvera, D. A. Levine, L. Norton, M. E. Robson, K. Offit, et al. Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis Ann. Surg. Oncol., September 1, 2007; 14(9): 2510 - 2518. [Abstract] [Full Text] [PDF]

				Y. Yin, C. Lin, and L. Ma Msx2 Promotes Vaginal Epithelial Differentiation and Wolffian Duct Regression and Dampens the Vaginal Response to Diethylstilbestrol Mol. Endocrinol., July 1, 2006; 20(7): 1535 - 1546. [Abstract] [Full Text] [PDF]

				E M Rosen, S Fan, and C Isaacs BRCA1 in hormonal carcinogenesis: basic and clinical research Endocr. Relat. Cancer, September 1, 2005; 12(3): 533 - 548. [Abstract] [Full Text] [PDF]

				M. Warren, C. J. Lord, J. Masabanda, D. Griffin, and A. Ashworth Phenotypic effects of heterozygosity for a BRCA2 mutation Hum. Mol. Genet., October 16, 2003; 12(20): 2645 - 2656. [Abstract] [Full Text] [PDF]

				A. R. Venkitaraman Functions of BRCA1 and BRCA2 in the biological response to DNA damage J. Cell Sci., March 12, 2002; 114(20): 3591 - 3598. [Abstract] [Full Text] [PDF]

				M. E. Moynahan, T. Y. Cui, and M. Jasin Homology-directed DNA Repair, Mitomycin-C Resistance, and Chromosome Stability Is Restored with Correction of a Brca1 Mutation Cancer Res., June 1, 2001; 61(12): 4842 - 4850. [Abstract] [Full Text] [PDF]

				N. Kirma, K. Gill, U. Mandava, and R. R. Tekmal Overexpression of Aromatase Leads to Hyperplasia and Changes in the Expression of Genes Involved in Apoptosis, Cell Cycle, Growth, and Tumor Suppressor Functions in the Mammary Glands of Transgenic Mice Cancer Res., March 1, 2001; 61(5): 1910 - 1918. [Abstract] [Full Text]