Kent W. Hunter, Ph.D.
- Center for Cancer Research
- National Cancer Institute
- Building 37, Room 4048
- Bethesda, MD 20892-4264
Dr. Hunter established the paradigm that metastatic progression of breast cancer has a significant inherited component. Using innovative strategies and cutting edge technologies he has identified a number of genes that contribute to inherited susceptibility to tumor dissemination. Dr. Hunter continues to pioneer the use of integrated genetic and genomic technologies to gain better understanding of the genes and cellular pathways that contribute to the metastatic process. Recent efforts include incorporating the knowledge gained from the genetic studies with novel therapeutic compounds or strategies to try to reduce metastatic burden in breast cancer patients.
Areas of Expertise
1) metastasis 2) breast cancer 3) genetics 4) genomics 5) systems biology 6) genetic susceptibility
The process of metastasis is of great importance to the clinical management of cancer because most cancer deaths are attributable to disseminated disease rather than the primary tumor. To better manage this critical clinical aspect of cancer it is necessary to gain a better understanding of the factors that lead to metastasis. To date the majority of metastasis research has focused on somatic alterations in tumor cells. However, in spite of decades of research and the identification of a large number of tumor cell-autonomous metastasis-associated genes, the process is still largely a mystery. Furthermore, it is still unclear whether metastasis is driven primarily by somatic events in the tumor or subject to functional variation at the level of the whole organism. Knowledge of this latter component may be critically important to the early identification of patients at risk for metastasis, which might alter their management and improve their prognosis.
The major goal of my laboratory is therefore to complement the existing and historic investigations of the tumor genome by characterizing the previously unexplored realm of the impact of constitutional genetic polymorphism on metastatic progression. To accomplish this, our laboratory initiated an investigation into the effects of constitutional genetic polymorphism on metastatic efficiency. Using the polyoma middle-T transgene-induced mouse mammary tumor model, we demonstrated that the genetic background upon which a tumor arose significantly influenced the ability of the tumor to form pulmonary metastases. Subsequently we have utilized a strategy that integrates population genetics analysis with a variety of genomic tools to begin to identify and characterize the polymorphic genes that drive metastatic susceptibility. To date we have identified more than 10 genetic factors that predispose individuals to develop metastatic disease. Unexpectedly, considering the complexity of the metastatic cascade and the genome, a number of these factors have been shown to directly interact at either the protein level or by direct transcriptional control level. The convergence of these studies on common subcellular complexes provides greater confidence of the role of these factors in tumor progression.
Currently the Hunter laboratory is further expanding our repertoire of tools to include the latest mouse genetic tools as well as high throughput sequencing and epigenetic analysis to provide greater depth for candidate gene discovery and characterizations. Inclusion of these resources will enable increased understanding of the higher order interactions and mechanisms underlying metastatic disease in both the primary tumor epithelium and surrounding tumor-associated stroma. Better understanding of the factors driving metastatic disease will likely lead to better clinical interventions to reduce cancer associated morbidity and mortality.
Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels
Kent W. Hunter, Ph.D.
Dr. Hunter received a B.S. in biochemistry with Highest Honors from the Pennsylvania State University in 1985 and a Ph.D. in Biology from the Massachusetts Institute of Technology in 1991. He was an associate member at the Fox Chase Cancer Center from 1996 to 1999. In 1999, he joined the NCI ( former Laboratory of Population Genetics) as an Investigator. He joined the Laboratory of Cancer Biology and Genetics in 2007 and was promoted to Senior Investigator. In 2015 Dr. Hunter was appointed Deputy Lab Chief and acting Co-Lab Chief in 2017.
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Sipa1 is a candidate for underlying the metastasis efficiency Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1modifier locus Mtes1
Previously, we demonstrated the presence of loci in the mouse genome that significantly influenced mammary tumor metastatic efficiency. Here we present data supporting the signal transduction molecule, Sipa1, as a candidate for the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes revealed a non-synonymous animo acid polymorphism in Sipa1 which has a significant effect on the Sipa1 RapGAP function. Spontaneous metastasis assays using cells ectopically expressing or knocked down for Sipa1 demonstrate that metastatic capacity is correlated with cellular Sipa1 levels. Examination of human expression data is consistent with the role of Sipa1 concentration in metastasis. Together these data suggest that the Sipa1 polymorphism is likely to be at least one of the genetic polymorphisms responsible for the Mtes1 locus. This is also, to the best of our knowledge, the first demonstration of a constitutional genetic polymorphism having a significant impact on tumor metastasis.
Nature Genetics, 37, 1055-1062
An Epistatic Interaction Controls the Latency of a Transgene-Induced Mammary Tumor
Previous studies from our laboratory demonstrated that the latency, tumor growth, and metastatic progression of polyoma middle T-induced mammary tumor in an FVB/NJ inbred mouse background could be significantly altered by the introduction of different genetic backgrounds. In this study we extend these findings by mapping a number of interacting quantitative trait loci responsible for the changes in phenotype. Introduction of the I/LnJ inbred genetic background into the FVB/NJ-PyMT animal significantly accelerated the appearance of the primary tumor (35 vs. 57 days postnatal, p < 10(-7)). A backcross mapping panel was established, and loci responsible for the tumor acceleration were detected on Chrs 15 and 9. Examination of the genotype/phenotype correlation revealed that the FVB/NJ but not the I/LnJ allele of the Chr 15 locus was associated with tumor acceleration and was conditional on the presence of I/LnJ allele on Chr 9. These loci, designated Apmt1 and Apmt2, map to homologous regions associated with LOH in human breast cancer. These results suggest that allelic variants of genes in these regions may contribute to age of onset in human breast cancer.
Mammalian Genome 11: 883-9.