BioWorld International Correspondent

LONDON - The long-sought "third gene" for breast cancer has finally been found - and it has a clear role in sporadic cases of breast and ovarian cancer.

The international consortium of researchers that discovered the gene, which members have called EMSY, showed how it interacts with BRCA2, a gene known to play a role in familial breast cancer. Interfering with the interaction between EMSY and BRCA2 could give rise to new drugs to treat most cases of breast cancer, the researchers predict.

Tony Kouzarides, who led the project at the Wellcome Trust/Cancer Research UK Institute at the University of Cambridge, said: "Discovering such an important new gene is very exciting and gives us the piece in the jigsaw we've been looking for. It's taken us six years to get here, but it's been well worth the effort."

He added: "We will now have a much more sophisticated image of the genetic changes triggering breast and ovarian cancer in women who haven't inherited a high risk of cancer, but develop it anyway. It's going to give us new lines of investigation and, potentially, exciting angles of attack."

The consortium, which has members in the UK, Canada, the Netherlands and France, is now trying to discover what other genes are involved in sporadic breast cancer, by studying other candidate genes that are deleted or amplified in sporadic breast cancers.

Kouzarides told BioWorld International, "We now suspect that there may be one or a few pathways that cause breast cancer, and therefore that disrupting these pathways will be important for many breast cancers, not just familial ones."

The consortium has published its findings in the Nov. 26, 2003, issue of Cell, in a paper titled "EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer."

Until this latest discovery, BRCA1 and BRCA2 were the only genes known to have a major involvement in breast cancer. They play a role in the majority of cases of familial breast cancer. But only about 5 percent of cases of breast cancer run in families, and despite much research, scientists have been unable to pin down exactly how BRCA1 and BRCA2 cause the disease.

What is known is that BRCA2 has a domain that activates transcription, and that its protein product localizes to sites of DNA repair. The consortium set out to search for sequences of DNA that interact with BRCA2, with the result that they were able to identify the new gene.

Kouzarides said: "We know that the protein product of EMSY also localizes to sites of DNA repair, and we have found that it binds to the domain of BRCA2 that activates transcription. So it appears that EMSY turns off the function of BRCA2."

That fits with what is known about BRCA2 in patients with inherited breast cancer, he said, because the binding domain of BRCA2 is missing in some of those families.

Further studies by the consortium showed that the EMSY gene was amplified in 70 out of 551 samples of breast tumors, or 13 percent. In 49 of them there were more than five copies of EMSY per cell.

The samples were collected between 1976 and 1990, and data were available on how long the women had survived and whether their breast cancers had recurred. Analysis showed that women whose cancer had not spread to their lymph nodes at the time of diagnosis, and whose tumors showed amplification of the EMSY gene, survived without recurrence for a median of 6.4 years, while those whose tumors did not have EMSY amplification survived without recurrence for a median of 14 years. Surprisingly, however, there appeared to be no difference in disease-free survival between those who had EMSY amplification and those who did not, among women who were node-positive at diagnosis.

The authors wrote, "We conclude that EMSY amplification identifies a subset of breast cancers associated with a poor prognosis."

The team also looked for amplification of EMSY in ovarian cancers. They found this feature in 17 percent (62 of 360) of high-grade (malignant) carcinomas, but in none of the 110 low-grade or borderline ovarian cancers. EMSY amplification was either absent or very rare in a further study of more than 250 other cancers from a wide range of primary sites.

Carlos Caldos, team leader in the Cancer Research UK Department of Oncology, said: "This discovery should help us in the development of new, targeted treatments against breast and ovarian cancers, particularly as cancers with high levels of the new gene seem to behave in a similar way to inherited forms. EMSY could also form the basis for new types of predictive test."

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