breast cancer cells

Fluorescent image of human breast cancer cells | NIH

For the first time, researchers from Yale have identified the molecular mechanism by which mutations in the BRCA1 gene can increase a person’s risk of developing breast or ovarian cancer. The paper, published in Nature this week, comes after more than 20 years of research into the gene since its initial discovery in 1994 and may hold the key to improving drug therapies available for patients.

Ever since the discovery of BRCA1, and that of its relative BRCA2 (identified in 1995), scientists have been unable to pin down the mechanism by which it is able to increase cancer risk. It was understood that a healthy copy of the gene was necessary for tumour suppression and DNA repair, which explained how a faulty copy could result in cancerous mutations following typical DNA damage. Earlier this year, researchers were able to identify why the genes were linked to cancers in specific tissues and linked the mutated gene’s activity to the breakdown of a tumour suppressing protein, but the exact activity of the mutated gene remained a mystery.

Regardless of their activity, it was originally believed that BRCA mutations (both type 1 and 2) accounted for around 7-8% of breast and ovarian cancer cases. More recently, however, it has been thought that the percentage is much higher, as it’s been found that the BRCA genes can be silenced without carrying any mutations within the genes themselves.

“There have been about 14,000 papers written about BRCA1, and you would think we already know everything about the gene, but we don’t,” said Patrick Sung, DPhil, Professor of Molecular Biophysics and Biochemistry and of Therapeutic Radiology at Yale School of Medicine and senior author of the paper.

In this study, the team have been able to identify an interaction between the BRCA1 and BARD1 genes, which results in the recruitment of the exact genetic sequence required for DNA repair. They demonstrated that when the two genes interact, they facilitate the generation of a single-stranded template, which in turn recruits a BRCA2-PALB2 tumour suppressing complex and a recombinase enzyme, RAD51. Healthy BRCA1-BARD1 complexes are able to enhance the activity of RAD51, whereas the mutated complex demonstrates significantly weaker interactions with the enzyme. Without this interaction, homologous recombination and DNA repair in the cells was impaired.

angelina jolie

The “Angelina” effect is the term given to the sudden increase in BRCA testing that followed actress Angelina Jolie’s elective double mastectomy after finding out she had a high risk of breast cancer. 

It is hoped that this new research will make it easier to predict a person’s risk of developing breast cancer. In recent years, due in no small part to the ‘Angelina effect’, BRCA testing has been at the forefront discussions surrounding clinical genomics and this hasn’t been without controversy. Questions about who should be receiving testing and who should be paying for these tests continue to circulate with great frequency. This research may be the first step into helping us to overcome these problems.

“Defining the mechanism of the BRCA-dependent DNA repair pathway will help scientists design drugs to kill cancer cells more efficiently,” said Sung. “Understanding this mechanism will provide the predictive power for doctors trying to establish a patient’s personal risk of developing cancer.”