Mutated Suppressor Gene Leads to a Type of Breast Cancer

MONDAY Dec. 10, 2007 -- Scientists believe they've discovered how mutations in the cancer-susceptibility gene called BRCA1 can cause some breast cancers.

Basal-like breast cancers (BBCs) represent 10 percent to 20 percent of all breast cancers. They generally have a poor prognosis and are difficult to treat, the researchers said.

The researchers found that inherited mutations in the BRCA1 gene deactivate another gene known as PTEN, which helps to suppress tumors. This suppressor gene is deactivated by the mutated BRCA1 gene's failure to repair a break in the PTEN gene's DNA, the scientists said.

The loss of the PTEN gene's tumor-suppressing ability allows increased cell activity that increases tumor growth. That action "can convert the cell from being a well-behaving entity to a bad citizen," said study co-author Dr. Ramon Parsons, a professor of medicine and pathology at Columbia University's College of Physicians and Surgeons.

"This is a very important finding, because this type of breast cancer doesn't have a type of therapy targeted at this point," Parsons said. Basal-like or triple negative tumors don't have receptors for the hormones estrogen and progesterone or the protein HER2, which most breast cancer therapies target, he said. Drugs that can target the pathway related to mutated PTEN genes "may be a way we can improve the survival for women with these basal-like tumors," he added.

Parsons said several pharmaceutical companies already are developing drugs to do just that.

"My guess is there's going to be a huge bolus of clinical trials with these drugs in the next couple of years," he said. "Since there's going to be such a large variety of compounds, my hunch is one or more will be effective." By effective, Parson said he doesn't mean one of them will offer a cure, but the drugs in the right combination could lead to a cure.

The development of these drugs also may be important for other types of cancers that can involve deactivating the PTEN gene, Parsons said.

The study results were published online Dec. 9 in the journal Nature Genetics.

Parsons said the discovery of the PTEN deactivation "was kind of a real long-term detective story." For 10 years, researchers have been trying to understand how the mutation in the BRCA1 gene can cause breast cancer. Instead of using traditional gene-sequencing techniques, Parsons and his colleagues looked for physical breaks in the PTEN gene. "PTEN is actually physically broken in half, we estimate, in 30 to more than 50 percent of the BRCA1 tumors," he said.

Dr. Jeffrey Weitzel, an associate professor of medical oncology at the City of Hope Comprehensive Cancer Center in Duarte, Calif., said the study by Parsons' team "helps us understand what's under-appreciated in the complex nature of tumor changes."

Andrew Godwin, director of the clinical molecular genetics laboratory at the Fox Chase Cancer Center in Philadelphia, added: "As we move towards personalized health care [and] medicine, identifying the cadre of genetic defects in a given breast tumor will likely influence how that patient is ultimately treated."

More information

For more on breast cancer, visit the U.S. National Cancer Institute.

Posted: December 2007


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