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Lucy M. Anderson, Ph.D., D.A.B.T.

Laboratory of Comparative Carcinogenesis Head, Cellular Pathogenesis Section Senior Investigator National Cancer Institute at Frederick Building 538, Room 205B Frederick, MD 21702-1201 Phone:   301-846-5600 Fax:   301-846-5946 E-Mail:   andersol@ncifcrf.gov

Biography

Dr. Anderson received her A.B. from Bryn Mawr College and her Ph.D. from the University of Pennsylvania in biology, with postdoctoral work in biochemistry at the University of Minnesota Medical School. She developed a program in carcinogen metabolism and perinatal carcinogenesis at the Memorial Sloan-Kettering Institute. She joined the NCI in 1982 and has continued studies of the mechanisms of tumorigenesis.

Research

Cellular Pathogenesis in Animal Models of Human Cancer Risk Mechanisms

Useful insights into the mechanisms of causation and development of cancers, and possible strategies for prevention and therapy, may be provided by studies of homologous risk situations in experimental animals. Adenocarcinomas are the most common form of human lung cancer, and these are well modeled by the comparable neoplasm in mice. The K-ras gene is frequently mutated in both human and murine lung adenocarcinomas. We are investigating the role of normal and mutated K-ras protein in growth control and malignancy of the lung. Secondly, increasing incidences of certain childhood cancers have led to interest in exposures of parents, including preconceptional exposures, as part of the etiology. We are investigating the mechanism of preconceptional carcinogenesis.

Cellular Mechanisms in the Development of Lung Adenocarcinomas
Currently research is based on three aims. (1) If K-ras protein has a role in controlling cell growth and differentiation, how does this work? What extracellular signals activate it, and how is the message passed downstream? We are utilizing microarray analysis to characterize genes with altered expression after K-ras activation and in malignant cells. (2) How does mutation in K-ras protein contribute to tumorigenesis? In addition to possible abnormality in downstream signal passage, mutant K-ras protein, which is in a permanently activated state, increases intracellular reactive oxygen and in DNA strand breaks. At low levels of mutant K-ras expression, most of the ROS appears to be generated by cyclooxygenase 2; with higher levels, a rac1 pathway is also involved. (3) If K-ras protein is not driving proliferation in tumor development, what is? With the discovery that transforming growth factor-alpha is secreted by malignant but not nontransformed mouse lung type 2 cells, an autocrine signaling pathway involving the ErbB3 and 4 receptors and phosphatidyl inositol 3-kinase was implicated and found to be generally present in human lung adenocarcinoma cells. Use of both antisense and siRNA constructs demonstrated the importance of this pathway for both cell division and motility.

Mechanisms of Preconceptional Carcinogenesis
Pursuing the hypothesis that the mechanism of preconceptional carcinogenesis is epigenetic, we have found that exposing male mice 2 weeks before mating to the occupational metal and nutritional supplement chromium(III) has led to alterations in both body weight and average serum thryoid hormone. Microarray analysis of gene expression in livers of the offspring has revealed changed expression of a number of genes in correlation with the altered serum T3 levels. Representational difference analysis was utilized to demonstrate that chromium(III) exposure of male mice caused hypomethylation in sperm in the gene for ribosomal RNA, which has a role in growth and cancer. This confirms an epigenetic mechanism. In general, this highly novel phenomenon has considerable potential to influence the physiology of offspring and the risk of many conditions in addition to cancer including asthma, obesity, and diabetes.

This page was last updated on 6/11/2008.