Cancer gene MYC shown to activate gene involved in metastasis

September 12, 2005

PHILADELPHIA--The cancer gene MYC is among the most commonly overexpressed oncogenes in human cancers. Most human cancers demonstrate high levels of MYC or its biological partners, including those of the breast, ovaries, lung, prostate, and skin, as well as leukemias and lymphomas. MYC is a regulator of other genes--a transcription factor--and scientists have been working for more than two decades to identify its target genes in order to understand how MYC causes so many cancers.

Now, scientists at The Wistar Institute have shown that MYC activates a gene called MTA1, which has been demonstrated by other researchers to regulate metastasis in a variety of cancers. While researchers have been exploring the possibility of blocking MTA1 to prevent metastasis, it was not previously known how MTA1 becomes activated in the first place. The study adds to the emerging picture of MYC's role in cancer development and progression and identifies the pathway linking MYC and MTA1 as an area for further exploration into the genetics of metastasis. The study appears in Proceedings of the National Academy of Sciences and is available in the journal's online "Early Edition."

"We and others have been working to understand what genes MYC turns on to cause malignant transformation," says Wistar associate professor Steven B. McMahon, Ph.D., senior author of the study. "Understanding metastasis is critical because patients rarely die of primary tumors--metastasis usually causes cancer deaths. Now, we have linked the well-known oncogene MYC to this target gene, MTA1, a key regulator of metastasis. Most importantly, if we block MYC's ability to turn on MTA1, we block tumor formation. This is critical because it identifies a point in the metastasis pathway that can be targeted therapeutically."

Like the MYC cancer gene, MTA1 has been shown to play a role in a wide range of cancers, including breast and lung cancers and lymphomas. With the help of Wistar's genomics facility headed by associate professor Louise C. Showe, Ph.D., McMahon and his colleagues sifted through nearly 10,000 genes before identifying MTA1 as a MYC target.

Among the pressing issues still to be resolved is understanding precisely why MYC's activation of MTA1 leads to metastasis. In spite of the work still to be done, the first generation of drugs that inhibit MTA1 and its partners is already being developed, and McMahon's study may inform this work. McMahon's laboratory at Wistar continues to study other target genes of MYC in order to elucidate more fully how this oncogene acts in such a wide range of cancers.
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The lead author of the study was Xiao-yong Zhang, Ph.D., a postdoctoral fellow in McMahon's Wistar laboratory. Other Wistar co-authors include associate professor Anthony J. Capobianco, Ph.D., postdoctoral fellow Lauren DeSalle, Ph.D., and graduate student Jagruti H. Patel. Senior author McMahon is an associate professor in Wistar's Gene Expression and Regulation Program. Co-authors at the University of Pennsylvania School of Veterinary Medicine were Andrei Thomas-Tikhonenko, Ph.D., and Duonan Yu, M.D., Ph.D. Funding for the work was provided by the National Institutes of Health and the Commonwealth University Research Enhancement Program of the Pennsylvania Department of Health.

The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center focused on basic and translational research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools. News releases from The Wistar Institute are available to reporters by direct e-mail upon request.

The Wistar Institute

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