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Gene Mutation Spreads Breast Cancer

Researchers find mutations knock our tumor supressors

December 12, 2007

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Scientists from Columbia University and Sweden’s Lund University have shed new light on how mutations of a gene – BRCA1 – can lead to breast cancer. The findings show that BRCA1 mutations can cause cancer by knocking out a powerful tumor suppressor gene known as PTEN.

The new study, to be published in Nature Genetics, was led by Ramon Parsons, M.D., Ph.D., the Avon Foundation Professor of Medicine and Pathology at Columbia University College of Physicians and Surgeons and Åke Borg, Ph.D., professor of oncology at Lund University.

“These findings are exciting because ever since the link was established between BRCA1 and breast cancer more than 10 years ago, we have been frustrated by our lack of understanding about how mutations in this gene cause breast cancer. We have been stymied by our limited resources to treat these cancers, which are associated with very poor prognoses," Parsons said. "Now that we know that PTEN is involved, we finally have a target for therapy for these cancers.”

Parsons is director of the Avon Foundation Breast Cancer Research Laboratory and director of the Breast Cancer Program of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital.

PTEN mutations promote runaway tumor cell growth by increasing the activity of a series of different proteins in the cell known as the PTEN/PI3K pathway. Shutting down any one of those proteins could potentially stop growth of the cancer. Investigational therapies to shut down proteins in the PTEN pathway are currently in Phase I clinical trials.

Parsons and his research team made the connection between BRCA1 and PTEN using techniques to search for physical chromosome breaks within the PTEN gene – a technique that had never before been used. Previous searches for PTEN mutations in BRCA1 tumors had looked for conventional mutations and failed to turn up any abnormalities.

The researchers scanned 34 biopsies taken from women with BRCA1 tumors. The PTEN gene had been split in two, but inadequately repaired in about one-third of the cancers. In some cases, entire sections of the gene were missing; in others, one-half of the gene was reattached to other regions on the chromosome.

These types of large chromosomal mistakes stem directly from the tumor’s lack of BRCA1, a gene that is normally involved in the repair of such damage. In breast cancers from women with normal BRCA1, such large mutations in PTEN were rarely detected.

Parsons estimates that about 50 percent of BRCA1 breast cancers will be found to harbor mutated PTEN once a complete analysis of chromosomal mutations is done.

Breast cancer tumors caused by BRCA1 are known as basal-like or triple-negative because these tumors usually lack estrogen, progesterone, and HER2 receptors, which are needed for most breast cancer treatments to be effective. Basal-like breast tumors are found in 10 to 20 percent of women with non-hereditary breast cancer (meaning, not caused by a genetic mutation in BRCA1 or another gene), and the researchers found that PTEN is also lost in the majority of these breast tumors as well.

“Our results point to PTEN as a major player in both hereditary and non-hereditary basal-like breast cancer, a finding that may now be exploited to develop new therapeutic strategies to improve outcomes for women with these aggressive tumors,” said Dr. Saal, who at the time of the research, was a fellow in Parsons’ Avon Foundation Breast Cancer Research Laboratory.

The researchers also predict that other cancer genes besides PTEN are targeted by BRCA1.

“By using the same techniques we used to find gross chromosomal rearrangements in PTEN, we hope to start identifying additional mutated genes involved in the development of breast cancer,” said Parsons.

“These kinds of mutations that break tumor suppressors in half may turn out to be common in many kinds of carcinomas, particularly those with deficiencies in DNA repair pathways similar to BRCA1, a question that only a systematic search can answer,” said Dr. Saal.

“Similar research is underway in tumors from carriers of germline mutations in BRCA2, the other known major breast cancer susceptibility gene,” said Dr. Borg. “BRCA2 has a role downstream in the same DNA double strand break repair pathway as BRCA1, but tumors from BRCA2 mutation carriers have a quite different phenotype compared to BRCA1 tumors, less often involving PTEN loss. However, like BRCA1, BRCA2 tumors have an instable genome with massive chromosomal aberrations, suggesting that other genes may be targeted.”

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