The overall goal of my research is to study the genetics of susceptibility to carcinogen exposure using mouse models. Susceptibility to environmental carcinogens is a function of multiple poorly penetrant genes that modify the propensity for tumor development. Mouse models of genetic susceptibility for development of specific tumors have been proven to be useful experimental tools for identifying and characterizing such genetic factors.
We are using two tumor model systems to identify and characterize genes that influence susceptibility to carcinogen-induced cancer in mice. One of the mouse models we have used to identify tumor-susceptibility loci is the 2-stage mouse skin tumor model. The 2-stage model of skin carcinogenesis involves an initiation step in which mice are treated with a single subcarcinogenic dose of a carcinogen followed by a promotion step in which initiated mice are exposed to multiple applications of a promoting stimulus such as 12-O-tetradecanoylphorbol-13-acetate (TPA). Sensitive mice develop premalignant papillomas. Studies indicate that genetic factors that influence papilloma formation primarily act at the promotion step. In collaboration with Dr. John DiGiovanni (University of Texas), we have examined TPA sensitivity in genetic crosses of sensitive DBA/2 or C3H mice with resistant C57BL/6 mice to identify genes that control promotion susceptibility. The results indicate that TPA susceptibility is a multigenic trait and we have mapped four susceptibility loci in this model. We have developed congenic mouse strains for one of these loci, Psl1 (promotion susceptibility locus 1). Analysis of these congenic strains revealed that Psl1 is a complex locus with at least four subloci affecting TPA promotion susceptibility. We have identified one gene, Gsta4, which underlies the effects of one sublocus, Psl1.2. Furthermore, we found that polymorphisms in the human GSTA4 gene are associated with increased susceptibility to the development of non-melanoma skin cancer. Studies are currently underway to better understand the role of Gsta4 in skin tumor promotion susceptibility and to identify and characterize additional genes that underlie Psl1 subloci.
We have recently begun to use a systems genetics (genetical genomics) approach to identify genes that modify susceptibility to skin tumor promotion, also in collaboration with Drs. DiGiovanni and Jianjun Shen (University of Texas MD Anderson Cancer Center, Science Park). As a part of this study, we have determined the susceptibility of 31 BxD recombinant inbred mouse strains that were developed from crosses of C57BL/6 with DBA/2 mice. As expected, these strains range in susceptibility to skin tumor promotion by TPA from resistant to hyperespondive. Genetic analysis of tumor response in these strains has identified several additional tentative TPA susceptibility loci. Additional studies are underway, examining the susceptibility of these strains to other promoting agents. Furthermore, we are in the process of developing gene expression networks in the epidermis by analyzing global gene expression in the epidermis of each of these strains. We will also develop gene expression networks in the epidermis from mice treated with diverse promoting agents. The ultimate goal of these studies is to identify genes that affect susceptibility to diverse promoting agents.
The other mouse tumor model examines the genetics of susceptibility of mice to N-methyl-N-nitrosourea (MNU)-induced thymic lymphomas. MNU susceptibility is a multigenic trait involving at least three genes mapping to chromosomes 1, 4, and 7. Recent studies using a haplotype mapping approach have narrowed two of these loci to chromosomal regions containing approximately ten genes each. Further studies are planned to identify and characterize high quality candidate genes that underlie these loci.
Pharmacology & Toxicology
College of Pharmacy
The University of Texas
107 W. Dean Keeton
Austin, TX, USA
Email Address: pharmtox
"Drugs, the Brain and Behavior" is co-authored by Dr. Carlton Erickson, the college's associate dean for research and graduate studies, and Dr. John Brick, executive director of Intoxikon International.
Andrea Gore is named to the SEBM Distinguished Scientist Award.