Untangling triple negative breast cancer

10 May 2010
Posted by Chris Smith.

Breast cancer survival is a real success story for science - now around 80 per cent of women survive for at least five years, compared with just half back in the 70s. But most of this success is in cancers that are fuelled by female hormones, which can be treated with hormone-blocking drugs, or by the HER-2 receptor, which can be blocked with the drug Herceptin. But there are also so-called "triple negative" cancers, which are much harder to treat, where survival is poorer. 

Breast self-examinationNow new research published in the journal Nature today from an international team, led by Cancer Research UK's Madalena Tarsounas in Oxford, Jos Jonkers in the Netherlands and Shridar Ganesan in the US, has discovered why these cancers may be resistant to chemotherapy and radiotherapy - as well as an intriguing link to the breast cancer gene BRCA1.

The faulty BRCA1 gene is found in hereditary breast cancer, where lots of women in the same family have the disease.  Also, around 9 out of 10 triple negative breast cancers are in women with faulty BRCA1, so there's clearly a link.  Sometimes these BRCA1-deficient cancers respond to radiotherapy and chemotherapy - particularly with platinum-based drugs such as carboplatin and cisplatin. But often the tumours develop resistance to treatment and start growing again. Tarsounas and her colleagues wanted to find out why.

The researchers started by looking at cells grown in the lab that lacked BRCA1. Contrary to what you might think, these cells actually don't grow well at all - it's the combination of faulty BRCA1 with other faulty genes that makes cancer cells grow. The researchers then used a  clever trick to randomly knock out genes in the BRCA1-deficient cells, to hunt for genes that made the cells grow again.

They found several - but the most interesting one was a gene called 53BP1, which is normally involved in helping cells to repair damaged DNA. Then they went on to discover that while cells lacking just BRCA1 can be killed with cisplatin or radiotherapy, cells lacking both BRCA1 and 53BP1 were resistant to treatment. So this explains how these cancers may develop resistance to therapy.

The scientists also looked at more than 1,800 samples from breast cancer patients, analysing 53BP1 levels and other characteristics. They discovered that most triple negative cancers also had low levels of 53BP1, suggesting the gene was faulty. And 53BP1 was also faulty in most of the cancers from women with BRCA1 faults.

This research tells us that BRCA1-deficient triple negative breast cancers with low levels of 53BP1 are likely to be resistant to radiotherapy and chemotherapy. So this could possibly be developed into a test to help doctors to decide what sort of treatment to give to women with these types of tumours.

And if we can find out exactly how loss of 53BP1 causes cancer cells to become resistant to treatment, it might reveal new targets for drugs to improve the effectiveness of chemotherapy and radiotherapy and overcome resistance, which would help to save lives.

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