Environmental Cancer FIRG
Leader: Dr. William Kaufmann, CEHS Director of Interdisciplinary Research and Professor of Pathology and Laboratory Medicine, UNC School of Medicine
The 1 million new cases of skin cancer in the US each year represent the nation’s greatest burden of environmental cancer. CEHS members have a strong record of research accomplishment in understanding the mechanisms of solar radiation carcinogenesis. Current projects include pre-clinical studies of skin carcinogenesis; a study of the effects of UV-induced DNA damage on DNA replication in human melanocytes; participation in the international Genes, Environment and Melanoma (GEM) study; and a study of how cell cycle checkpoints protect against UV-induced chromosomal damage.
Center members are also using a genetically modified mouse (with mutations in Ras oncogenes and deletion of p16 and ARF tumor suppressor genes) to induce melanomas with high penetrance and low latency to understand the role UV light plays in inducing melanomas. The melanoma FIRG will building on its strength in development of animal models to create a mouse with targeted inactivation of RFPC genes in skin melanocytes. The melanoma program also employs a systems biology approach with development of computational models to visualize the networks of protein interactions in the DNA damage response, predict the effects of UV-induced DNA damage on cell cycle progression and induction of chromosomal aberrations, and create a mathematical model of DNA damage G2 checkpoint function.
CEHS members have yielded important information on gene-environment interactions in breast carcinogenesis. One significant result was the finding of interactions between specific genotypes (CYP1A1) and PCB exposure. Others included the demonstration that cigarette smoke interacted with mutations in nucleotide excision DNA repair genes to increase risk of breast cancer. And through participation in the Long Island Breast Cancer Study, CEHS member Dr. Marilie Gammon found an association between heavily cooked meat and breast cancer risk but no effect from pesticides.
Other recent projects examined gene-nutrient interactions in breast cancer, and the effects of glutathione-S-transferase gene polymorphisms and exposures to polynuclear aromatic hydrocarbons and organochlorine pesticides on breast cancer incidence and survival (K01-CA104517, L30-CA124219). In addition, CEHS researchers have found substantial inter-individual variation in DNA damage response among breast cancer cases and matched controls. However, no association between DNA repair and risk of breast cancer has been identified. Current studies are investigating whether dietary methyl donors may influence breast cancer risk through epigenetic effects (R01-CA109753).
Dr. Charles Perou has been studying signatures of gene expression in breast cancers and discovered the triple-negative (ER-, PR-, Her2-) or basal-like subtype. This work is important as Drs. Perou and Robert Millikan have shown that the basal-like subtype is over-represented in African-American women. Because the basal-like subtype has poor prognosis, this racial difference may account for some of the racial disparities in breast cancer mortality, where younger African American women have a breast cancer mortality rate twice that of younger white women. It is particularly important to determine the mechanisms for the predisposition to basal-like breast cancer among African-American women.
To address the pressing health disparities among African American, rural, and low-income women in North Carolina, Dr. Millikan has initiated a new cycle of enrollment in the Carolina Breast Cancer Study (CBCS), one of the largest black breast cancer databases in the United States. The study will enroll an additional 2000 patients from 44 North Carolina counties, conduct in-person interviews, construct tissue microarrays, and obtain medical records and DNA samples. CBCS3 is contributing to a multi-institutional genome-wide association study of breast cancer in African Americans.
Funded by NIEHS Grant # P30 ES010126