ABSTRACT
Breast cancer is a multifactorial disease that develops as a result of interactions among genetic, environmental, and hormonal factors. Multiple genetic derangements are believed to be involved in the pathogenesis of breast cancer, including the inactivation of tumor suppressor genes and/or the disregulation of proto-oncogenes. Age, hormones, and environmental factors further influence these genetic derangements. Spontaneous and chemically induced animal models of breast cancer have been limited in their usefulness. The advent of targeted gene mutations has allowed for a more specific exploration of the pathogenesis of breast cancer by creating mouse models that mimic single or multiple gene alterations found in human mammary tumors. The genes targeted in these models include mouse mammary tumor integration sites and genes that encode for growth regulators, signal transduction proteins, cell cycle proteins, and cell matrix proteinases. In this review, I summarize tumor morphology and the relevance of each model to the pathogenesis and progression of human breast cancer. These models have great potential for elucidating the multistep process of mammary gland carcinogenesis and for contributing to the identification of novel therapeutic targets.
Subject(s)
Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/genetics , Animals , Animals, Genetically Modified , Genetic Engineering , Mice , Rats , Transgenes/geneticsABSTRACT
Women who inherit mutations in the BRCA2 cancer susceptibility gene have an 85% chance of developing breast cancer. The function of the BRCA2 gene remains elusive, but there is evidence to support its role in transcriptional transactivation, tumor suppression, and the maintenance of genomic integrity. Individuals with identical BRCA2 mutations display a different distribution of cancers, suggesting that there are low-penetrance genes that can modify disease outcome. We hypothesized that genetic background could influence embryonic survival of a Brca2 mutation in mice. Brca2-null embryos with a 129/SvEv genetic background (129(B2-/-)) died before embryonic day 8. 5. Transfer of this Brca2 mutation onto the BALB/cJ genetic background (BALB/c(B2-/-)) extended survival to embryonic day 10.5. These results indicate that the BALB/c background harbors genetic modifiers that can prolong Brca2-null embryonic survival. The extended survival of BALB/c(B2-/-) embryos enabled us to ask whether transcriptional regulation of the Brca1 and Brca2 genes is interdependent. The interdependence of Brca1 and Brca2 was evaluated by studying Brca2 gene expression in BALB/c(B1-/-) embryos and Brca1 gene expression in BALB/c(B2-/-) embryos. Nonisotopic in situ hybridization demonstrated that Brca2 transcript levels were comparable in BALB/c(B1-/-) embryos and wild-type littermates. Likewise, reverse transcriptase-polymerase chain reactions confirmed Brca1 mRNA expression in embryonic day 8.5 BALB/c(B2-/-) embryos that was comparable to Brca2-heterozygous littermates. Thus, the Brca1 and Brca2 transcripts are expressed independently of one another in Brca1- and Brca2-null embryos. Mol. Carcinog. 28:174-183, 2000.
Subject(s)
Fetal Death/genetics , Gene Expression Regulation, Developmental/genetics , Mice, Inbred BALB C/genetics , Neoplasm Proteins/physiology , Transcription Factors/physiology , Animals , BRCA1 Protein/deficiency , BRCA1 Protein/physiology , BRCA2 Protein , Base Sequence , Embryonic and Fetal Development/genetics , Female , Genes, BRCA1 , Genes, Lethal , Genetic Predisposition to Disease , Genotype , Mice , Mice, Inbred BALB C/embryology , Mice, Knockout , Molecular Sequence Data , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Transcription Factors/deficiency , Transcription Factors/genetics , Transcriptional Activation/geneticsABSTRACT
The mouse homologues of the breast cancer susceptibility genes, Brca1 and Brca2, are expressed in a cell cycle-dependent fashion in vitro and appear to be regulated by similar or overlapping pathways. Therefore, we compared the non isotopic in situ hybridization expression patterns of Brca1 and Brca2 mRNA in vivo in mitotic and meiotic cells during mouse embryogenesis, mammary gland development, and in adult tissues including testes, ovaries, and hormonally altered ovaries. Brca1 and Brca2 are expressed concordantly in proliferating cells of embryos, and the mammary gland undergoing morphogenesis and in most adult tissues. The expression pattern of Brca1 and Brca2 correlates with the localization of proliferating cell nuclear antigen, an indicator of proliferative activity. In the ovary, Brca1 and Brca2 exhibited a comparable hormone-independent pattern of expression in oocytes, granulosa cells and thecal cells of developing follicles. In the testes, Brca1 and Brca2 were expressed in mitotic spermatogonia and early meiotic prophase spermatocytes. Northern analyses of prepubertal mouse testes revealed that the time course of Brca2 expression was delayed in spermatogonia relative to Brca1. Thus, while Brca1 and Brca2 share concordant cell-specific patterns of expression in most proliferating tissues, these observations suggest that they may have distinct roles during meiosis.
