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New Study Reveals How BRCA1 Mutations Cause
cancer research
| New Study Reveals How BRCA1 Mutations Cause Breast Cancer Drugs in development may be effective for inherited disease |
Photo: Charles Manley |
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Although the link between BRCA1 and breast cancer was made more than 10 years ago, cancer researchers have not understood why BRCA1 mutations cause cancer. BRCA1 proteins are known to repair damage to DNA, but the failure to fix DNA damage cannot cause cancer by itself.
The new study reveals that one way BRCA1 mutations cause cancer is by knocking out a powerful tumor suppressor in the cell called PTEN. “Unlike the BRCA1 mutation, the mutation to PTEN is a “direct hit to a cell growth pathway,” says the study’s corresponding author Ramon Parsons, M.D., Ph.D, the Avon Foundation Professor of Medicine and Pathology. “Once a cell loses PTEN, it has a growth advantage over its neighbors and it is on the road to cancer.”
Dr. Parsons led one of the two teams that independently discovered the PTEN tumor suppressor in 1997. The new study, co-authored with Lao Saal, Ph.D., P&S’09, and Åke Borg, Ph.D., professor of oncology at Lund University, and others, appears in the December issue of Nature Genetics.
The discovery immediately evokes a way to attack BRCA1 breast cancers, which are almost always “triple-negative” tumors that are resistant to standard breast cancer treatments, including Herceptin. (Triple-negative tumors lack estrogen, progesterone, and HER2 receptors which are needed for most breast cancer treatments to work. They account for 10 percent to 20 percent of all breast cancers). Between 60 percent and 80 percent of women who carry a BRCA1 mutation will develop breast cancer at some point during their lives. Because the prognosis is poor, many young BRCA1 carriers are opting to have their breasts removed instead of waiting for cancer to appear.
The discovery also may help other women who have normal BRCA1 but similar triple-negative tumors. Many tumors, the researchers found, have also lost PTEN.
“The exciting thing about the PTEN lesions is that they open up new treatment strategies to explore, which could improve outcomes for women with these aggressive cancers whether they are inherited or not,” says Dr. Saal, the study’s first author. PTEN mutations promote runaway 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 cancer growth.
Because PTEN has already been identified as a critical player in multiple forms of cancer, drugs that shut down proteins in the PTEN pathway are in Phase I clinical trials. BRCA1 breast cancer trials could begin as soon as the drugs are proven safe.
Dr. Parsons says his research team made the connection between BRCA1 and PTEN because they used techniques to search for large chromosomal rearrangements in the PTEN gene, which had never been done. Previous searches for PTEN mutations in BRCA1 tumors had looked for only small mutations and failed to turn up any abnormalities. “Identifying these rearrangements would not have been possible without the support of the shared resources of the Herbert Irving Comprehensive Cancer Center and our collaboration with Hanina Hibshoosh, M.D., associate professor of clinical pathology, Vundavalli Murty, M.D., associate professor of pathology, and Dr. Borg,” says Dr. Parsons.
In the new search, the researchers scanned 34 biopsies from BRCA1 tumors. In about one-third of the cancers, the PTEN gene had been split in two but inadequately repaired. In some cases, entire sections of the gene were missing; in others, half of the gene was reattached to a completely different gene. These types of large chromosomal mistakes stem directly from the tumor’s lack of BRCA1, which would normally repair such damage. In breast cancer tissue from women with normal BRCA1, such large mutations in PTEN weren’t found.
Dr. Parsons estimates that about half of BRCA1 breast cancers will be found to harbor mutated PTEN once a census of chromosomal mutations is complete.
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, I think that we will start identifying these other genes soon,” Dr. Parsons says.
This research was supported, in part, by the Avon Foundation, OctoberWoman Foundation, and the NIH.
—Susan Conova
