Recent progress in our laborabory has been significant. During the past years we published the results of our first study of the effect of constitutional polymorphism influencing metastasis. We demonstrated that a single amino acid polymorphism in the gene Sipa1 could modulate the metastatic capacity of mouse mammary tumors by as much as ten-fold. Furthermore we demonstrated, using pilot human epidemiology studies, that polymorphisms in the human ortholog of this gene, SIPA1, were associated with lymph node status in human breast cancer. These findings were the first published example that genetic inheritance rather that mutation within tumors, plays a major role in progression of human cancer. More recently we have been extending these results to investigate the role of additional genes in the establishment of metastasis susceptibility. Two complementary approaches are being pursued. First, using the Sipa1 molecule as a nucleus, we are identifying and characterizing gene products that physically interact with the metastasis modifying protein Sipa1, with particular focus on those protein binding partners that interact with the polymorphic PDZ domain. Current efforts have revealed that at least three of the putative collection of candidate proteins demonstrate significant effects on metastasis in experimental systems, as well as evidence of a role in human breast cancer in pilot epidemiology studies. The second avenue of research is based on expression quantitative trait mapping. Using our highly metastatic mouse model and a complex trait genetics strategy, we have identified an additional 5 genes that demonstrated experimental associations with mammary tumor progression. Analysis of expression array data suggests that at least 4 of these genes may play a role in human breast cancer metastasis susceptibility, with 3 of the novel genes suppressing tumor progression, and one potentially increasing metastasis susceptbility. Using these complementary methodologies, we plan to continue our genetic and genomic analysis of the genome architecture associated with breast cancer tumor progression. The data generated in these studies will be further analyzed by state-of-the-art computational methods to further elucidate the complex interacting networks associated with metastatic progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CP010146-08
Application #
7593184
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2007
Total Cost
$1,614,453
Indirect Cost
Name
Division of Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hunter, Kent W; Amin, Ruhul; Deasy, Sarah et al. (2018) Genetic insights into the morass of metastatic heterogeneity. Nat Rev Cancer 18:211-223
Shukla, Anjali; Alsarraj, Jude; Hunter, Kent (2014) Understanding susceptibility to breast cancer metastasis: the genetic approach. Breast Cancer Manag 3:165-172
Simmons, John K; Amlin-Van Schaick, Jessica C; Geiger, Thomas R et al. (2012) Mouse genetics 2011: meeting report. Mamm Genome 23:225-31
Hunter, Kent W (2012) Mouse models of cancer: does the strain matter? Nat Rev Cancer 12:144-9
Alsarraj, Jude; Walker, Renard C; Webster, Joshua D et al. (2011) Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion. Cancer Res 71:3121-31
Hunter, Kent W; Alsarraj, Jude (2009) Gene expression profiles and breast cancer metastasis: a genetic perspective. Clin Exp Metastasis 26:497-503
Gordon, Ryan R; Hunter, Kent W; Sorensen, Peter et al. (2008) Genotype X diet interactions in mice predisposed to mammary cancer. I. Body weight and fat. Mamm Genome 19:163-78
Yang, Haiyan; Yu, Li-Rong; Yi, Ming et al. (2006) Parallel analysis of transcript and translation profiles: identification of metastasis-related signal pathways differentially regulated by drug and genetic modifications. J Proteome Res 5:1555-67
Hunter, Kent (2006) Host genetics influence tumour metastasis. Nat Rev Cancer 6:141-6
Hunter, Kent W; Crawford, Nigel P (2006) Germ line polymorphism in metastatic progression. Cancer Res 66:1251-4

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