Researchers Discover New Breast Cancer Gene
In October, CSHL cancer researchers Masaaki Hamaguchi and Michael Wigler published their discovery of a new tumor suppressor gene that is missing from or inactive in 60% of the breast cancer specimens they examined, and is also altered in lung cancer.
The study is significant in part because if focused on sporadic or non-heritable forms of breast cancer. Sporadic disease accounts for greater than 90% of all breast and other cancers, in contrast to heritable forms of cancer, which account for a relatively small percentage of the disease. (Annual U.S. morbidity and mortality due to breast cancer are 200,000 and 40,000 people, respectively. As a cause of cancer deaths cancer among American women, breast cancer is second only to lung cancer.)
The scientists use a gene discovery method pioneered by Michael (called Representational Difference Analysis or RDA) to detect the differences between the DNA of normal cells and breast tumors—differences that might contribute to tumor formation. This analysis, combined with other methods, identified a region of human chromosome 8 that was specifically deleted from the DNA of breast tumors.
Michael and Masaaki used a variety of criteria to home in on a single gene in this region of chromosome 8. They dubbed the gene DBC2, for deleted in breast cancer. Subsequent analysis confirmed that the DBC2 gene was either deleted, mutated, or not expressed in many of the breast tumors or breast cancer cell lines the scientists examined. Expression of the DBC2 gene was undetectable in 11 of 19 of such breast cancer specimens, and was also undetectable in 7 of 14 of lung cancer specimens examined. In contrast, expression of the DBC2 gene was detected in all of the normal tissue specimens examined, and in the vast majority of other cancer cell types examined (e.g. colon cancer).
To test whether restoring DBC2 gene expression was sufficient to restrain the growth of breast cancer cells that lack DBC2 expression, Masaaki engineered a breast cancer cell like to express either a mutated version of the DBC2 gene (originally identified in a breast tumor biopsy), or the normal DBC2 gene.
When expression of the mutated DBC2 gene was induced in the breast cancer cell line, the cells continued to grow in an unrestrained manner. However, when expression of the normal DBC2 gene was induced in the breast cancer cell line, the cells stopped growing. This finding indicated that restoration of DBC2 gene function is sufficient to restrain the growth of at least one breast cancer cell type.
Michael thinks it would be difficult to restore a normal DBC2 gene to cancer cells that lack it, say, by gene therapy. Instead, he believes that identifying other proteins "awakened" or activated by the loss of DBC2 expression in cancer cells, and inhibiting those proteins with new drugs, would be an excellent theraputic strategy. Such strategies based on identifying hyperactive molecules in cancer cells and inhibiting those molecules with drugs have recently begun to yield promising results.
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