A Wayne State researcher has received two federal stimulus grants totaling more than $775,000 to investigate the potential role of polychlorinated biphenyls (PCBs) in the progression of breast cancer and to delineate the role of a liver enzyme in the development of metabolic diseases such as heart disease, abnormal cholesterol metabolism and insulin resistant type II diabetes.

Melissa Runge-Morris, M.D., professor and acting director of the Institute of Environmental Health Sciences at Wayne State University and a resident of Detroit, Mich., received $418,000 from the National Institutes of Health. Her research group is investigating the effect of PCBs accumulated in breast tissue, beginning in the very early stages of development.

"We're trying to understand if normal levels of PCBs that one might be exposed to in the environment accelerate breast cancer progression," Runge-Morris said.

PCBs are a class of chemical compound that for many years was used in hundreds of industrial and commercial applications including electrical, heat transfer, and hydraulic processes. Although no longer commercially produced in the U.S., PCBs may be present in products and materials produced before their 1979 ban. PCBs do not readily break down, tending instead to persist in the environment, cycling among air, water and soil for long periods of time. They are not easily detoxified from the human body, instead accumulating and persisting in fatty tissue over extended periods of time. Research has provided conclusive data that PCBs cause cancer in animals, with studies in humans supporting their potential carcinogenicity.

Runge-Morris will study the effects of PCBs in normal human breast epithelial cells and in those that are more progressed toward cancer. She will use cell culture techniques and will transplant or "xenograft" cells into immunodeficient mice. Her studies are designed to determine whether PCBs activate key estrogen-responsive or reactive oxygen pathways implicated in breast carcinogenesis.
The cell culture and xenograft model for human breast cancer progression that is used by Runge-Morris' research team was developed by WSU investigators at the former Michigan Cancer Foundation. Runge-Morris said one of the advantages of this model is that it facilitates the exploration of the earliest stages of breast cancer development. "Many of the breast cancer cell lines that are currently studied represent more advanced stages of cancer," she said. "Our model, on the other hand, uses human breast epithelial cells that are practically normal to determine if exposure to PCBs or other environmental contaminants tips the balance toward cancer progression. It also takes advantage of the limited mouse lifespan, allowing us to determine if cancer develops at an accelerated rate."

Runge-Morris received a second stimulus grant for $357,461 to investigate the function of a liver enzyme that plays a central role in lipid metabolism. Disturbances in lipid metabolism set the stage for the emergence of metabolic diseases such as heart disease, liver dysfunction and insulin resistant type II diabetes.

The enzyme hydroxysteroid sulfotransferase, or SULT2A1, is known to metabolize hormones and detoxify drugs, chemicals in the environment and carcinogens. Recent studies, however, suggest that SULT2A1 is also capable of metabolizing oxysterol intermediates of cholesterol metabolism.

Runge-Morris' lab uses primary cultured human hepatocytes and molecular biology approaches to characterize the enzyme's integrated role in a vast lipid metabolism network. "We want to understand exactly what controls the gene that encodes SULT2A1 because it may explain the diversity of responses that characterize drug, chemical, hormone and cholesterol metabolism in humans."

Results of the study will shed new light on diseases that occur as a function of disordered lipid metabolism. "Not everyone who is obese, for example, develops type II diabetes," Runge-Morris said. "We suspect this could be due to critical inter-individual differences in lipid metabolism. A better understanding of the molecular events that regulate the major players in lipid metabolism like SULT2A1 will provide us with the tools to recognize and prevent the development of serious metabolic diseases in humans."

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