Facilitator: Jeffrey Rosen (Baylor College of Medicine)
- Are currently available experimental models of breast cancer suitable to study whether environmental exposures cause cellular and molecular changes?
- What new technologies should be used to enhance our ability to improve existing models or create new models for mammary carcinogenesis?
Jeffrey Rosen introduced the fourth workshop discussion topic on the use of animal models to study environmental influences on breast cancer. Rosen focused on emerging mouse models as preferred alternatives to the well-established two-year rat bioassay. In general, animal models are important research tools because they allow for increased control over genetics and other variables. Recently developed technology for constructing mouse transgenics, knockouts, bitransgenics, and conditional or tissue-specific knockouts increases the advantages of the mouse as a model organism. These technologies can be used to analyze gain or loss of function mutants, genetic interactions and modifiers, and they facilitate development of preclinical models of breast cancer.
Mice have been generated with deficiencies in DNA repair genes and in genes that may play a role in breast cancer susceptibility (i.e., BRCA1, BRCA2, p53, Rad1, Rad9, ATM and others). Initial studies of p53 knockout mice indicate that p53 deficiency does not confer intrinsic susceptibility to breast cancer. However, mice expressing a mutant p53 allele in the mammary gland are susceptible to carcinogen-induced breast cancer. In addition, gamma-irradiated or progesterone-stimulated p53 null mammary epithelial cells are more tumorigenic than similarly exposed normal mammary epithelial cells.
Rosen suggested that new endpoints should be developed for studying breast cancer in animal models. Tumors are often measured as a late endpoint of carcinogenesis in the breast. Early signs of premalignant disease are lacking. Rosen described three models that can be used to help study preclinical breast cancer and identify markers of early disease: 1) a transgenic mouse expressing an oncogene; 2) a conditional knockout mouse of BRCA1 in the mammary gland; and 3) transplanted genetically engineered breast epithelial cells.
Hormonal signaling plays a significant role in breast development and in breast cancer. Hormone receptors and the cell specificity of their expression in breast is an important factor in hormone signaling mechanisms. Evidence from mouse models suggests that the normal breast responds to progesterone in a paracrine manner. This means that receptor negative cells proliferate in response to a signal from adjacent receptor-positive cells. Cancer may arise in cells that respond to hormone in an autocrine manner.
Rosen pointed out that mouse models could be engineered to facilitate research on mechanisms of breast carcinogenesis. The NCI mouse models initiative is not generating models for this purpose, because they are primarily generating mouse models for testing cancer intervention and treatment.
Key Discussion Points:
- Mouse models
Development of new mouse models is a priority area in breast cancer research. Engineered mouse models will facilitate research on specific pathways and components that contribute to breast cancer risk. Use of mice that are predisposed to carcinogen-induced breast cancer will require less time, less money and fewer animals. However, the animal models are not perfect and questions on how to engineer mouse models to make them "better" are needed. Additionally, tumors are different in women of different ages. The current animal model studies do not account for these differences.
- Mouse models in research
A question that arises is whether there is sufficient information and data to state that one specific animal model should be used for targeted breast cancer research or if several animal models should be used. It was suggested that different models should be used, since it is currently unclear which animal model is the "best" model or what constitutes the "best" model. Research could focus on models where the animals are sensitized so to increase the signal obtained in the results.
- Comparing mouse and human
NCI is beginning to develop extensive comparisons of mouse and human pathobiology for preclinical use. Additional work is needed in this area.
- Legal issues
Development of mouse models for breast cancer research may be hindered due to legal restrictions on certain mouse lines and technologies. NIEHS may be able to facilitate access to some proprietary materials for research purposes.