Delthia Ricks | Newsday

Scientists in Manhattan say they've discovered the fundamental way a key gene leads to a hereditary form of breast cancer and how that will aid in the hunt for new treatments.

Ever since the mid-1990s when BRCA1 was discovered, scientists had been stumped in attempts to unlock the door that hid why BRCA1 goes awry. First discovered as a significant cause of breast cancer in women of Ashkenazi Jewish descent, the gene, when mutated, researchers since have learned, is an important cause of breast cancer in women of many cultures, mostly those under 40 and some as young as their 20s.

Equally important, BRCA1 is associated with "triple negative" cancers, those lacking estrogen, progesterone and HER2 proteins on tumor surfaces. Today's most effective treatments require the presence of those proteins.

Now, scientists at Columbia University, collaborating with a team in Sweden, have found that a gene, dubbed PTEN, actually is involved in the cascade of genetic miscues that result in cancer. In some patients PTEN is mutated - broken - and incapable of functioning to prevent cancer. Normally, BRCA1 can fix a broken PTEN gene, but when that doesn't happen, a form of breast cancer that can prove extraordinarily difficult to treat occurs.

"Ever since the link was established between BRCA1 and breast cancer, we have been frustrated by our lack of understanding about how mutations in this gene cause breast cancer," said lead investigator Dr. Ramon Parsons. The absence of genuine understanding, he said, stymied efforts to effectively treat BRCA1 patients, who often have a poor prognosis.

But a finding by Parsons and a team of medical investigators in 1997 is paying dividends. In 1997, Parsons and colleagues discovered PTEN, revealing it as a potent tumor suppressor gene. That means, when healthy, PTEN applies the brakes, stopping the ill-fated events that lead to cancer. Now they know that, when crippled, PTEN cannot block the cancer-causing activities of a mutant BRCA1.

Parsons said defects in PTEN probably account for 50 percent of breast cancers in women who inherit a mutated BRCA1 gene. With PTEN so intimately involved, he added, drug developers now have a new target because a basic disease-causing mechanism has been uncovered. Results of the study were reported yesterday in the online edition of Nature Genetics.

Dr. Janice Lu, a breast cancer researcher and assistant clinical professor at Stony Brook University, said unmasking genetic defects involved in BRCA1 cancers is vital. "Women with BRCA1 and BRCA2," Lu said of two cancer-related genes, "have up to an 85 percent chance of developing breast cancer, and up to a 60 percent chance of ovarian cancer. So the mechanism is very important."

Like PTEN, BRCA1 when healthy "will protect us and repair [damaged] DNA," Lu said. She commended the work by Parsons and his collaborators because illuminating the molecular processes in hereditary breast cancer ultimately aids clinicians in its treatment.

Parsons underscored that an altered PTEN also is involved in certain brain and prostate cancers, and that discoveries involving PTEN are adding to a growing catalog of data.

Earlier this year, Dr. Hasan Korkaya of the University of Michigan showed how PTEN and HER2, another breast cancer gene, conspire in an especially aggressive form of breast cancer.

Road to cancer

How mutations to key genes can cause tumor cells to grow out of control.

NORMAL GENE

BRCA1 belongs to a class of genes that play a role in fighting tumors. When healthy, BRCA1 can repair or "sew" a damaged PTEN gene, another key tumor suppressor.

MUTATED GENE

When BRCA1 is damaged, it stops repairing PTEN, sending a signal to tumor cells to grow, leading quickly to cancer. Also, BRCA-A related tumors lack estrogen, progesterone and HER2 proteins, which are needed for most cancer treatments to be effective.