Epstein-Barr Virus Linked To Invasive Breast Cancer And Lymphoma; University Of Michigan Scientists Find Virus Releases Molecular Brake On Roaming Cancer Cells

In a paper published in the March 2001 issue of Nature Medicine, U-M scientists show how the Epstein-Barr virus alters the function of a cellular protein that normally suppresses the movement of malignant cells. When this natural brake on cell migration is disabled by the virus, cancerous breast and lymphatic cells are free to metastasize or spread.

"This is the first evidence of a human virus associated with the development of cancerous tumors targeting a cellular protein to promote the migration of malignant cells," says Erle S. Robertson, Ph.D., who directed the study. Robertson is an assistant professor of microbiology and immunology in the U-M Medical School and a researcher in the U-M's Comprehensive Cancer Center.

"The Epstein-Barr virus is associated with many human cancers -- including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease and invasive breast cancer," Robertson says.

The virus is very common. More than 90 percent of adults show signs of previous viral infection. Adolescents infected with the acute phase of the virus can develop infectious mononucleosis, but usually the body's natural immune response forces the virus to revert to its latent phase -- where it hides inside the nucleus of immune cells called lymphocytes without producing any symptoms.

Even though the virus is endemic in humans, Robertson emphasizes that most cells infected by the virus may never become malignant. Additional genetic factors are required to trigger development of cancer. Should cancer develop, however, Robertson says the risk of metastasis may be higher in individuals previously exposed to the virus.

"People with aggressive forms of cancer are most vulnerable and should be checked to determine the status of previous viral exposure when physicians are choosing the most appropriate treatment for them," Robertson says. "It also would be wise to closely monitor people with a history of active Epstein-Barr viral infection for early signs of cancer."

In the study, Chitra Subramanian, Ph.D., a U-M research fellow, and Murray A. Cotter II, a U-M graduate student, investigated a gene from the Epstein-Barr virus called EBNA-3C, and the protein produced by infected lymphocytes when this gene is expressed. The EBNA-3C protein was found in all EBV-infected cancerous lymphocytes in the breast cancer and lymphoma cell lines analyzed in the study.

U-M researchers discovered that the EBNA-3C protein binds to a human metastatic suppressor protein called Nm23-H1, which is found in all human cells. "The interaction between the two proteins disables Nm23-H1's natural ability to keep malignant cells in their original location thereby promoting metastasis," explains Robertson.

"We have mapped the binding site to one region of the viral protein EBNA-3C and hope in future research to identify the exact location on the targeted protein," Robertson says. "Our goal is to find the binding site and discover how to block the interaction between these two proteins.

"If we succeed, physicians could one day be able to treat primary breastand lymphatic cancers, as well as other cancers associated with the Epstein-Barr virus, without worrying about malignant cells spreading to other parts of the body."

The research study was funded by the Leukemia and Lymphoma Society of America and the National Cancer Institute.