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Newly Discovered Genes Implicated in Breast Cancer
  
By Donna L. Bernstein

A newly identified complex of genes called BRCC appears to work with the BRCA1 and BRCA2 genes, which, when mutated, are associated with an increased risk of developing breast and ovarian cancers. Researchers find that BRCC is overactive in more than half of the breast cancer tumors they examined.

Approximately 5 to 10 percent of breast cancers are inherited and the rest are considered sporadic, arising spontaneously or from environmental causes. Many but not all women with inherited forms of the disease have mutations in BRCA1 or BRCA2, and researchers are searching for additional genes involved in the disease. Two new studies report progress.

A new study implicates the BRCC complex of genes, which may be responsible for sporadic cancers that do not run in families, and are not associated with the BRCA1 or BRCA2 genes identified in the 1990s.

The researchers believe that BRCC36 and BRCC45, two genes in the BRCC complex, could be long-sought additional breast cancer susceptibility genes. “My gut feeling is that we should find mutations in BRCC36 and BRCC45 in hereditary breast cancers,” says Ramin Shiekhattar of the Wistar Institute in Philadelphia and one of the study’s authors.

The researchers, led by Wistar scientist Yuanshu Dong, report their findings in Molecular Cell. They also postulate that although BRCC does not repair DNA directly, when it’s working it may put the brakes on the cell cycle and allow DNA repair to take place. The BRCC complex appears to tell the cell’s degradation machinery to destroy p53, a well-known gene involved in cell division. When this malfunctions, uncontrolled cell growth occurs and errors in DNA accumulate, leading to cancer.

In an additional finding, an international consortium of researchers has identified a novel gene that may begin to link interactions of hereditary breast cancer genes and some sporadic forms of breast cancer and ovarian cancer. The gene, named EMSY, can bind to and switch off BRCA2, potentially accelerating the cancer development process. When they examined tumor cells, the researchers found EMSY was abnormally active in 13 percent of sporadic breast cancers and in 17 percent of sporadic ovarian cancers.

Led by Tony Kouzarides of Wellcome Trust/Cancer Research UK Institute in Cambridge, the researchers, reporting in Cell, also found that cancer patients with increased amounts of EMSY faced a poor prognosis, particularly those with node-negative breast cancer. Patients with amplified EMSY survived an average of 6.4 years, compared to 14 years for women with normal amounts of EMSY in their tumors. This suggests that the gene may be useful in estimating prognoses.

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Dong, Y. et al. Regulation of BRCC, a Holoenzyme Complex Containing BRCA1 and BRCA2, by a Signalosome-like Subunit and Its Role in DNA Repair. Molecular Cell, 12, 1–20 (November 2003).

 

Hughes-Davies, L. et al. EMSY Links the BRCA2 Pathway to Sporadic Breast and Ovarian Cancer. Cell 115, 523-535 (November 2003).

 

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