How mutant BRCA2 causes cancer

Scientists believe they have uncovered one of the cancer-causing secrets of the breast cancer gene BRCA2.

Faulty BRCA2 not only causes breast cancer in up to 60 per cent of women who inherit it, but also raises the risk of ovarian and prostate cancer – yet scientists have never understood its precise mechanism of action.

But writing in the journal Nature¹, researchers from Cancer Research UK, the Medical Research Council and the Wellcome Trust reveal how damaged BRCA2 loses control of a key molecule that helps hold our genetic information together.

Their discovery, which is causing waves throughout the scientific community, has exciting implications for drug development.

BRCA2 normally controls a molecule called Rad51, which is involved in repairing DNA and keeps the genes in a cell intact. Researchers at the University of Cambridge studied precisely how the BRCA2 protein molecule, produced from the gene, interacts with Rad51 and how the process goes wrong when BRCA2 is faulty.

They discovered that BRCA2 has eight ‘Velcro strips’, each of which attaches to Rad51 using a multitude of tiny molecular hooks. By sticking to the Rad51 molecule, BRCA2 may direct it accurately to sites of DNA damage and control its ability to carry out repair.

Several cancer-causing versions of BRCA2 are damaged within these ‘Velcro strips’, hampering the ability of BRCA2 to control Rad51 and so causing cells to develop potentially cancerous mutations.

Team leader Professor Ashok Venkitaraman, of the Hutchison/MRC Research Centre in Cambridge, which is joint funded by Cancer Research UK and the Medical Research Council, says: “When the BRCA2 gene is faulty, a cell’s genetic information becomes increasingly unstable, making it more likely that cancer will develop.

“Understanding the nuts and bolts of BRCA2’s function should in the future allow us to develop new types of anti-cancer drug – although progress in this direction will take more time and continued effort.”

Researchers believe that drugs to block the action of BRCA2 could, strangely enough, become crucial tools in the fight against cancer.

The ability of BRCA to control Rad51 helps cells combat the killing effect of DNA damage caused by cancer therapies such as radiation. Even cancer-causing versions of BRCA2 may retain some of this ability.

Now that scientists know precisely how BRCA2 interacts with Rad51, they should be able to find ways of totally disrupting this interaction. This could make cancer cells more sensitive to killing by radiation or other therapies.

Sir Paul Nurse, Chief Executive of Cancer Research UK, says: “By focusing in on the fine detail of the cancer-causing process, this study has given us an exciting leap forward in our understanding of the disease on a molecular level. The work is not just an important advance scientifically, but should also have a real impact on the future development of cancer treatments.”

ENDS

1. Nature420 (6913) (Nov 21, 2002)

Note to Editors:

The BRCA2 gene was itself discovered by an international team led by a Cancer Research UK scientist, Professor Mike Stratton, at The Institute of Cancer Research in Sutton, back in 1995.