Link Found in Inherited Breast Cancer, Other Cases

Researchers reported Tuesday that they have finally linked inherited forms of breast cancer with seemingly random cases, and said their findings shed more light on the causes of the disease.

They found a protein that may disrupt the BRCA1 and BRCA2 genes that cause an inherited form of breast cancer. It may explain why some patients who do not have mutations of these genes get breast cancer.

The new protein, called EMSY, may cause many so-called sporadic cases of breast and ovarian cancer and may offer a new target for drugs to fight the disease, they report in this week’s issue of the journal Cell.

The BRCA genes, named for their role in breast cancer, help repair damaged DNA before it can make a cell turn cancerous. In people whose genetic code differs in certain ways -- those with the mutations -- the repair process goes wrong.

Ten percent of Jewish breast cancer patients in the United States carry mutations of BRCA1 or BRCA2.

More than 1.2 million people will be diagnosed with breast cancer this year worldwide and it kills 40,000 a year in the United States alone.

Most cases are sporadic, meaning they are caused by genetic mutations that do not seem to have been inherited.

A team of British, Canadian and French researchers were looking for some kind of link between BRCA-associated breast cancers and the other 90% or so of cases.

Dr. Tony Kouzarides and colleagues from the Wellcome Trust/Cancer Research U.K. Institute of Cancer and Developmental Biology in Cambridge looked at 551 women with sporadic breast cancer.

Their BRCA genes looked normal, but a protein, called EMSY, was overactive in some.

The women whose EMSY protein was overactive had unusually aggressive breast cancer -- in fact, similar to women with BRCA2 mutations.

“Clearly, breast cancer with amplifications of EMSY are bad guys,” Dr. Carlos Caldas, a University of Cambridge oncologist who worked on the study, said in a telephone interview.

In several hundred Canadian breast cancer patients from British Columbia, women with overactive EMSY survived an average of 6.4 years while those whose tumors were similar but without extra EMSY lived 14 years.

Caldas and colleagues found EMSY was overactive in about 13% of sporadic cases of breast cancer and 17% of ovarian cancers, Caldas said.

Both EMSY and BRCA seem to be DNA repair proteins. “Perhaps they interfere with each other,” Caldas said.

“The next step is to refine the function of the EMSY protein at the biochemical level,” he added. “We want to identify what is special about these tumors, why they are so aggressive clinically.”

In a second report, a team at the Wistar Institute in Philadelphia found that the BRCA1 and BRCA2 genes make proteins that combine with others to form a complex called BRCC. BRCC fixes damaged DNA.

Writing in the journal Molecular Cell, they said they also found two new proteins that are part of BRCC. One of them, which they called BRCC36, was involved in sporadic breast cancers.

“We know that BRCA1 and BRCA2 are normally tumor suppressor genes that, when mutated, can lead to cancer, but they only account for a fifth of all hereditary breast cancers and about 5% of breast cancers overall,” Ramin Shiekhattar, who headed the study, said in a statement.

“The BRCC36 gene and the other genes that factor into the creation of the BRCC complex are good candidates for additional breast cancer susceptibility genes.”