How BRCA1 Mutations Cause Breast Cancer Revealed for First Time

An international team of researchers led by Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center and Sweden’s Lund University has, for the first time, revealed how mutations in the BRCA1 gene lead to breast cancer. Findings show that one way BRCA1 mutations cause cancer is by knocking out a powerful tumor suppressor gene known as PTEN.

The new study will be published online on the Nature Genetics website on Dec. 9, 2007: www. nature.com/ng. It will appear in the January print issue of this journal. The study 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. The paper’s first author was Lao Saal, Ph.D. (now finishing his medical degree at Columbia University College of Physicians and Surgeons).

“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. Now that we know that PTEN is involved, we finally have a target for therapy for these cancers,” said Dr. Parsons, the study’s corresponding author. Dr. 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.

In 1997, Dr. Parsons led one of the two teams that independently discovered the PTEN, one of the most important tumor suppressor genes altered in breast cancer, as well as in brain and prostate cancers. PTEN is now recognized to be mutated in about 30 percent of all cancers, making it the second most mutated gene in cancer after p53. Knocking out PTEN sends a strong pro-growth signal on tumor cells. This is unlike the BRCA1 mutation, which only predisposes the cells to accumulate genetic damage and sends an indirect signal for cell growth. “Once a cell loses PTEN, it has a growth advantage over its neighbors and starts on the road to cancer,” said Dr. Parsons.

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.

How the BRCA1 Mutation Mechanism Was Pinpointed

Dr. 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.