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 published online on the Nature Genetics website on Dec. 9, 2007. 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. He is also a member of Columbia's Institute for Cancer Genetics.
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.
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.
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.
Dr. 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 Dr. 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 Dr. Parsons.