Extensive epidemiological work and clinical genetics on families indicated that there must be a gene on chromosome 17(q) whose heritable mutation increased susceptibility to breast and ovarian cancer. With positional cloning, BRCA1 (BReast CAncer1) was identified (Futreal et al., 1994) and subsequently many different mutations have been described in diverse populations, including Ashkenazi Jewish, Japanese, Korean, African, and Chinese families (Katagiri et al., 1996; Okobia and Bunker, 2003; Ademuyiwa and Olopade, 2003; Lynch et al., 2004; Judkins et al., 2005; Kim et al., 2006; Song et al., 2006).
Rodent models in which the homolog of BRCA1 is knocked out (Brodie and Deng, 2001; Zan et al., 2003) have elucidated a variety of environmental, hormonal, and genetic factors that increase the penetrance of BRCA1 mutations causing breast and ovarian cancer. Such work is impossible in humans. For example, conditional inactivation of BRCA1 in the epithelial tissue of mice led to cancer development in organs other than the breast and ovary (Berton et al., 2003). Other genes have been identified and manipulated, such as ataxia telangiectasia mutated (Atm) heterozygosity and p53, demonstrating their interaction with BRCA1 to increase mammary cancer (Bachelier et al., 2005; Bowen et al., 2005). In this mouse model, even though mammary tumors were estrogen receptor negative, removing the ovaries nonetheless reduced the development of mammary tumors late in the life span. However, in a wild-type rat model, phytoestrogen-rich diets increased the BRCA1 mRNA, but not protein produced by the tumor suppressor gene. Thus, the rodent models have the potential to manipulate the environmental, hormonal, and genetic mechanisms affecting the expression of BRCA1 mutations in order to determine which are mediators and only modulate their effect on mammary tumorigenesis.
New models may not be necessary, but they could be useful. The quest for new and improved models should continue. However, promising existing models also should be nurtured, fine-tuned, and developed further.
Animal models have a great deal to offer in furthering our understanding of the impact of interactions among social, behavioral, and genetic