Session 1: The Developing Mammary Gland: Application of Genetics & Toxicogenomics
Facilitator: Philip Iannaccone (Northwestern University)
Discussion Questions:
How can we more fully understand the molecular underpinnings of the development of the mammary gland? Can this be enhanced by a targeted toxicogenomics/proteomics approach?
How can the creation of databases or other resources facilitate our understanding of the molecular architecture of breast tissue in a way that would support future studies of the environmental carcinogenesis?
What additional work in breast cancer genetics could shed light on important gene-environment interactions?
Introduction
The first session of the workshop focused on mammary gland development and the usefulness of high throughput toxicogenomics-based approaches in breast cancer research. Phillip Iannaccone introduced this topic of discussion, indicating that the new "-omics" technologies, including transcriptomics, genomics, proteomics and metabolomics are important and powerful tools for breast cancer research. Transcription profiling may be the most important method currently available. Proteomics, genomics also are likely to be useful in the future. Tissue arrays, robotic in situ hybridization and "knockdown" mutants (i.e., RNAi, siRNA, and RNA morpholinos) also may be particularly useful in breast cancer research. Iannaccone suggested that it is key to understand the timing and importance of proliferative mechanisms during breast development. Studies in mice and humans indicate that mammary gland development involves precisely regulated periods of cell proliferation (i.e., during human puberty). Several cell signaling pathways are important during breast development, especially the sonic hedgehog pathway, which involves Patched, Gli and Cyclin D2. The cross talk between mesenchymal and epithelial breast tissues also is important during breast development. Iannaccone listed several environmental factors that are worthy of additional study in relation to breast cancer susceptibility, including cigarette smoking, ionizing radiation, and compounds that signal through the aryl hydrocarbon receptor (i.e., dioxin). Iannoccone emphasized that research on all of these questions and issues could be facilitated by high throughput toxicogenomics methods.
Key Discussion Points:
High- throughput toxicogenomics-based methods in breast cancer research
In general, workshop participants suggested that high throughput toxicogenomics methods, especially transcription profiling, are likely to be useful in breast cancer research. In particular, gene expression profiling will be useful to understand the signaling pathways that play roles in breast development and breast carcinogenesis. Samuel Wilson (NIEHS) pointed out that high throughput analysis of gene expression will make it possible to simultaneously analyze many gene expression pathways that contribute to breast development and many environmental agents that could impact these pathways, thus making possible a comprehensive approach to breast cancer research. It also was pointed out that animal model systems are powerful tools to use in combination with toxicogenomic methods, and specialized model systems will support the optimal use of toxicogenomics methods in breast cancer research.
Design and implementation of a breast cancer research database
Several workshop participants emphasized that a well-planned database/data repository is needed to serve the breast cancer research community. Significant concern was expressed about database design and planning: the database should be designed prospectively and in a manner that allows effective cross-platform data comparison and easy access (i.e., web-based). It was suggested that NIEHS could take a leadership role in design and implementation of a breast cancer research database and provide associated informatics support for the database. Ray Tennant (NIEHS) indicated that the Chemical Effects on Biological Systems (CEBS) database is being established by the National Center for Toxicogenomics (NCT) at NIEHS, and this database may serve some of the needs of the breast cancer research community.
Coordinated research activities and databases
Workshop participants recommended that breast cancer research efforts should be actively coordinated throughout the scientific community. Concern also was noted about pooling existing information on toxicogenomics and proteomics into complementary databases, or even combining the data into a single database. It was suggested that the NIH could take the lead to combine various sources (i.e., NCI Mouse Model Consortium, NLM gene array database) and standardize the information.
An image database for breast cancer research
Barbara Davis (NIEHS) suggested that an image database might be useful, particularly for facilitating cross-species comparisons and monitoring markers of the developing breast.
Improved tissue procurement network
Several workshop participants expressed concern about the inadequate supply of human breast tissue for research purposes. This problem is particularly severe with regard to normal tissue from prepubescent girls for studying normal human breast development. Trauma victims are one of the main sources of normal human tissue for research, but this resource is extremely limited. New and existing breast cancer research initiatives need better tissue resources, including an improved tissue procurement network and improved access to the tissue samples that are available. It also was suggested that standardization of tissue procurement be considered, since many collected samples cannot be used due to differences in procurement and storage procedures.
Better understanding of the normal human breast
More research is needed on normal human breast biology and development. Breast cancer only can be understood in the context of a comprehensive understanding of the mechanisms that regulate breast growth, development and function during all life stages of a normal female. For example, it is not clear what happens biologically at early pregnancy to protect against breast cancer development. It is not clear if environmentally induced changes survive after an early preganancy/lactation event or if these protections work by eliminating early cellular insults.
Build on existing knowledge of breast cancer genetics
A definitive role is established for specific genes in hereditary breast cancer (i.e., BRCA1, BRCA2) and other genes are suspected of playing a role in sporadic breast cancer. This knowledge should be used to identify and characterize additional factors that act in the same or pathway or by a similar mechanism of action.
Social factors in the etiology of breast cancer
Nancy Krieger (Harvard School of Public Health) pointed out that social factors should be considered in research on breast cancer. In particular, Krieger questioned whether the social environment of lab animals might influence the outcome of the studies. Several workshop participants indicated that the uniformity of the lab environment might negate its potential to introduce bias in study outcome. However, it was acknowledged that the social conditions of lab animals might influence experimental outcome, and that this possibility is usually ignored because social factors are extremely complex and difficult to analyze. It was also pointed out that social factors might affect human breast cancer incidence and etiology.
Subpopulations
Researchers noted that toxicogenomic results would not be observed in all subpopulations of cells and organisms (e.g., mouse, human). Studies with these unique subpopulations, and using different techniques, should be considered. Additionally, studies in different mouse strains should be performed for comparison of modifying effects (e.g., protein expression, enzyme activity and expression, phenotypes, responses to pharmaceuticals) in different genetic backgrounds.
Mammary ducts
Hormone receptors in mammary ducts are a critical determinant of mammary gland development. Patterning of these receptors through all stages of life will provide greater insight into mouse and human mammary development. Questions that need to be addressed include, but are not limited to, where the receptors are, which cells are dividing in response to the receptors, and what do exposures to agents specifically do to alter normal cellular events.
Breast stem cell research
Breast stem cells are distributed throughout the breast. Their role during breast carcinogenesis is poorly understood and warrants further study. Breast stem cells are also useful because they can be engineered and used in transplantation.
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