Member of training programs:
and Training Grants:
Space for 2 graduate students
Funding for 1 graduate student (1 pending)
Research interests: Molecular genetics of breast cancer susceptibility
Research synopsis: Our laboratory integrates basic and applied molecular genetics in the study of breast cancer. Current studies focus on the genetic identification and molecular characterization of loci which modify the risk for breast cancer. Our work relies on rodent models, human breast cell cultures and large collections of DNAs from breast cancer case-control studies.
Genetic Identification of Breast Cancer Risk Loci in Women
We initially identified many breast cancer susceptibility loci using quantitative trial locus mapping in a rat model of breast cancer. After identifying the human genomic regions that were homologous to those in the rat. We then evaluated those human regions for association with breast cancer using DNA from ~12,000 women. For example, we found that the MCS5A (Mammary Carcinoma Susceptibility 5A) loci modulated breast cancer risk in both rats and women (PNAS 2007).
Most Risk Loci are Located in Non-coding DNA
Thus far, all loci that have been fine-mapped in the rat are located in non-coding DNA. Most are quite far from the 5’ start site of surrounding genes. One, in fact, is in the middle of a large gene desert. A similar situation is found in humans susceptibility loci. We are focusing on how these non-coding loci act to modify risk. We are focusing on the role of chromatin folding as well as the generalized function of large gene deserts.
We found that the MCS5A locus required two interacting elements on the same chromosome located ~60 kB apart to be functional for reducing breast cancer risk. We used a novel “3C” assay to study details of DNA folding in the region and found that the 3-dimensional structure of the DNA bring these two elements closer to each other than would be predicted by the linear distance between them. We are currently identifying the molecular function of each element together with the role of their interaction.
The MCS5A non-coding region acts to control the expression of the ubiquitin ligase FBXO10. The target(s) for this ligase is unknown. We are using many approaches to study its function ranging from yeast 2-hybrid studies to characterizing FBXO10 knockout mice.
Immunology – Immune Surveillance
We have found that the FBXO10 differential regulation by the MCS5A locus occurs exclusively in T-cells. We are working to define how this gene changes the immune phenotype of T-cells making them better able to control emerging breast cancers.
Most of the above-described research is reductionist in nature. In contrast, there is also a utility to combine these reductionist data together with appropriate human genomic data (e.g., results of genome-wide association studies for breast cancer) into testable mathematical models. We have formed a collaborative group that includes molecular biologists, geneticists, statisticians, informatics researchers, and epidemiologists, together with their graduate students and post-docs, to develop and test these integrative genomic models. We will focus on using these models to hypothesize functional activities of susceptibility loci and their interactions with environmental agents.
Current graduate students: Adeline Veillet (Genetics)
Past graduate students: Stephan Woditschka (Genetics 08); Stephanie Hesselson (Genetics 07); plus ~12 others
Lab Size: 8-10
Samuelson, D. J., Hesselson, S. E., Aperavich, B. A., Zan, Y., Haag, J. D., Trentham-Dietz, A., Hampton, J. M., Mau, B., Chen, K.-S., Baynes, C., Khaw, K.-T., Luben, R., Perkins, B., Shah, M., Pharoah, P. D., Dunning, A. M., Easton, D. F., Ponder, B. A., and Gould, M. N. Rat Mcs5a Is a Compound Quantitative Trait Locus with Orthologous Human Loci That Associate with Breast Cancer Risk. Proc. Natl. Acad. Sci. USA, 104: 6299-6304, 2007.
Amos-Landgraf, J. M., Kwong, L. N., Kendziorski, C. M., Reichelderfer, M., Torrealba, J., Weichert, J., Haag, J. D., Chen, K.-S., Waller, J. L., Gould, M. N., and Dove, W. F. A Target-selected Apc-mutant Rat Kindred Enhances the Modeling of Familial Human Colon Cancer. Proc. Natl. Acad. Sci. USA, 104: 4036-4041, 2007.
Cotroneo, M. S., Haag, J. D., Zan, Y., Lopez, C. C., Thuwajit, P., Petukhova, G. V., Camerini-Otero, R. D., Gendron-Fitzpatrick, A., Griep, A. E., Murphy, C. J., Dubielzig, R. R., and Gould, M. N. Characterizing a Rat Brca2 Knockout Model. Oncogene, 26: 1626-1635, 2007.
Key Campus Affiliations:
Genetics Training Grant
Molecular Pharmacology Training Grant
Environmental Toxicology Program
UW Cancer Center