Researchers discover new breast cancer gene

Scientists at Cold Spring Harbor Laboratory have discovered 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 it 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.

The scientists, led by Dr. Michael Wigler, used a gene discovery method he pioneered (called Representational Difference Analysis or RDA) to detect the differences between the DNA of normal cells and breast tumors—differences which 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.

The researchers used a variety of criteria to zero 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, the scientists engineered a breast cancer cell line to express either a mutated version of the DBC2 gene (originally identified in a breast tumor biopsy) or the normal DBC2 gene.

When the 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 the 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.

The study appears in the October 15, 2002 issue of the Proceedings of the National Academy of Sciences.

Dr. Wigler, who was joined in this study by lead author Dr. Masaaki Hamaguchi, says that finding what proteins might be activated by the loss of DBC2 expression in cancer cells is an important next step if effective therapies based on DBC2 are to be developed. Inhibitors of such proteins could mitigate the effects of the loss of DBC2 function in cancer cells, however, much additional work would be required to achieve such a goal, says Wigler.

Dr. Wigler’s group has previously used the RDA gene discovery strategy to identify another tumor suppressor gene associated with sporadic breast cancer, called PTEN. DBC2 now joins PTEN as a tumor suppressor gene that may play a major role in the development of breast and other cancers.

Annual U.S. morbidity and mortality due to breast cancer are 200,000 and 40,000 people, respectively.

Written by: Communications Department | publicaffairs@cshl.edu | 516-367-8455