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BRCA1 protein

BRCA1 is faulty in many hereditary breast cancers

Over the years, Cancer Research UK has helped transform breast cancer treatment – now 8 out of 10 women survive their disease for more than 5 years, compared with 5 out of 10 women in the 1970s.

Most of this progress has been made in so-called hormone-sensitive cancers – those that are fuelled by the hormones oestrogen or progesterone.  These tumours tend to respond well to hormone-blocking drugs such as tamoxifen. And the drug trastuzumab (Herceptin) can be very effective for women whose cancers produce large amounts of a molecule called HER-2.

But there is a significant group of breast cancers that lurk in the shadow of this success. Around 15 out of every hundred cases are “triple negative” tumours –  they don’t respond to hormone treatment, and they don’t have high HER-2 levels. This leaves limited options for treatment.

Writing in the journal Nature Structural and Molecular Biology this week, Cancer Research UK-funded scientists in Oxford, and their international colleagues, have made an important discovery that could help doctors decide how best to treat women with triple negative breast cancer. And their findings also shed light on tumours caused by inherited faults in the BRCA1 gene.

The BRCA1 connection

Regular readers of the blog may recognise BRCA1, as we’ve mentioned it several times before (for example, here, here and here). BRCA1 is involved in repairing damaged DNA, and faults in the gene are responsible for most  cases of hereditary breast and ovarian cancer.

For reasons that aren’t entirely clear, women with faulty BRCA1 are more likely to develop triple negative breast cancer – one study found that nine out of ten women with triple negative breast cancer also had faulty BRCA1. And, sadly, women with the faulty gene are also more likely to get cancer at a younger age.

In some cases, these cancers respond well to treatment with platinum-based drugs, such as carboplatin and cisplatin, to PARP inhibitors or radiotherapy. But they can develop resistance to the treatment and start to grow again, cutting the chances of survival.

Working with an international team of collaborators, Dr Madalena Tarsounas (from our Gray Institute for Radiation Oncology and Biology) set about trying to discover why this happens.

To start with, the team studied laboratory-grown cells that lacked BRCA1. Although it seems a bit counter-intuitive (as BRCA1 is associated with cancer), these cells actually don’t grow very well because they can’t repair damage to their DNA. But, unlike these ‘artificial’ BRCA1-less cells,  cancer cells with faulty BRCA1 also have faults in other genes that allow them to compensate, so they ignore DNA damage and grow out of control.

The scientists used a clever technique (called “insertional mutagenesis”) to randomly ‘hit’ genes in these BRCA1-deficient cells, stopping them from working, then looked for cells that started growing well. They discovered that when a gene called 53BP1 was damaged, in addition to faulty BRCA1, then the cells grew vigorously.

What is 53BP1?

Although it lacks a glamorous name, 53BP1 plays an important role in enabling cells to respond to damage to their DNA, by switching on another, well-known cancer gene called p53 – the “guardian of the genome”.

Having discovered that 53BP1 could help BRCA1-less cells to grow, Dr Tarsounas and her team then looked in more detail at how the loss of the gene affected the BRCA1-deficient cells. As mentioned above, cells lacking BRCA1 often respond to the chemotherapy drug cisplatin, at least initially. But the scientists found that cells without BRCA1 and 53BP1 were no longer susceptible to the drug and continued to grow.

Next, the researchers looked at the effect of radiotherapy on cells with just faulty BRCA1, and cells with both gene faults. Radiotherapy could kill cells with a fault in BRCA1 alone, but it was no longer effective against the cells with faults in both BRCA1 and 53BP1.

Taken together, these results tell us that faulty 53BP1 could play an important role in the development of drug  and radiotherapy resistance in hereditary breast cancer.

But that’s not all they found.

53BP1, BRCA and triple negative breast cancers

The researchers also analysed more than 1,800 samples taken from breast cancer patients, to look at 53BP1 levels and other characteristics.

They found that most samples of triple negative cancers  had very low levels of 53BP1 (suggesting the gene – or its control mechanism – was faulty). This was  especially true of those cancers that had spread through the body.  Very low 53BP1 levels were also found in cancers from women who had inherited a faulty BRCA1 gene.

These results are striking – they show that faulty 53BP1 is particularly common in aggressive and hard-to-treat triple negative breast cancers, and in tumour with faults in BRCA1. But what does this mean for patients?

The next steps

This paper tells us that BRCA1-deficient and/or triple negative breast cancers with low levels of 53BP1 are likely to be resistant to radiotherapy and chemotherapy. In the future, this could become a useful test to help doctors to decide what sort of treatment to give to women with these types of tumours.

And, perhaps more importantly, it gives us an important insight into some of the genetic pathways at work in triple negative and BRCA1-deficient breast cancer. We now need to find out exactly how loss of 53BP1 causes cancer cells to become resistant to treatment.

Uncovering this information will reveal new targets for drugs to improve the effectiveness of chemotherapy and radiotherapy and overcome resistance, helping to improve survival from these difficult-to-treat cancers.

Kat


Reference:
Bouwman, P. et al (2010). 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers Nature Structural & Molecular Biology DOI: 10.1038/nsmb.1831

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Comments

medical blog December 26, 2010

If the monopoly on the BRCA gene patent is broken by the current ACLU and patient supported lawsuit affordable testing should come soon.