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New study reveals for first time how BRCA1 mutations cause breast cancer
Date:12/9/2007

s, 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.

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 tumors 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.

Finding May Affect 50% of BRCA1 Breast Cancers & Lead to New Treatments

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.
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Contact: Elizabeth Streich
eas2125@columbia.edu
212-305-6535
Columbia University Medical Center
Source:Eurekalert

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