Genetic “fine-tuners” and breast cancer

Last year an international team led by Cancer Research UK scientists at our Cambridge Research Institute unveiled the results of a huge research project called METABRIC. They used advanced gene sequencing techniques to analyse the patterns of gene activity in breast tumours from thousands of women, revealing the molecular ‘signature’ of each tumour. The results showed that the disease could be divided into ten distinct subtypes, each with its own characteristics and outlook.

That work was just the beginning of the story. Since then, the researchers, led by Professor Carlos Caldas, have been delving into these subtypes in ever greater depth, trying to figure out what makes them different and how we can tackle each one more effectively.

In a new paper, published in the leading scientific journal Nature, the team took another look at the thousand breast cancer samples from the METABRIC study. But rather than looking at genes that bear the instructions to make proteins in our cells, the researchers focused instead on a set of genes that encode tiny lengths of RNA – a relative of the larger DNA molecules that makes up our genome.

In recent years it has become clear that these short pieces of RNA – known as microRNAs, or miRNAs for short – can help to control when and where protein-making genes are switched on or off, and they’re an increasingly hot topic in the world of cancer research.

And now it looks like they may be playing a role in controlling how the immune system responds to certain breast cancers.

Small but powerful

First discovered in the 1990s in tiny worms called nematodes, microRNAs act as molecular ‘switches’ inside cells, turning genes off when they’re not needed as well as fine-tuning gene activity levels. They’re made from chopping up much longer strings of RNA – a type of molecular ‘messenger’ in cells.

Many hundreds of different microRNAs have now been identified, and they can recognise and act on individual genes in various ways. And thanks to projects such as ENCODE, we also know there’s a lot more in the genome still to be discovered.

Researchers already know that cancer cells contain different levels of microRNAs compared to healthy cells – generally, they tend to be lower – and some types of cancer seem to have a characteristic microRNA fingerprint. This suggests that they could be useful for helping to diagnose or potentially even treat the disease.

Professor Caldas and his team wanted to find out whether the ten distinct subtypes of breast cancer they’d identified in the METABRIC study also had a telltale microRNA signature, and whether this matched up with the particular characteristics of that type.

Mapping microRNAs

In the largest study of its kind ever undertaken, the researchers looked at more than 850 different microRNAs in around 1,300 breast tumour samples taken from patients. These cancers had already been analysed as part of the METABRIC project, so plenty was known about them in terms of their genetic makeup, as well as how well they had responded to treatment.

The results of METABRIC showed that there are ten distinct subtypes of breast cancer, referred to by the researchers as iClust1 through to iClust10. Many of these subtypes have a lot of changes in their DNA, with pieces copied many times or going missing altogether.

Because the instructions that make microRNAs are encoded in our DNA, scattered amongst the 30,000 or so proper genes that make up our genome, the scientists wondered how they might be affected by this genetic chaos. And, in turn, they wanted to see whether any resulting changes in the microRNAs were having a knock-on effect on gene activity.

Finding a pattern

After scanning through a huge amount of data, looking at the levels of 850 different miRNAs in nearly 2,000 samples, the team found that only one particular subtype of breast cancer – known as ‘iClust4’ – had a consistent pattern of characteristic microRNAs. iClust4 is the most common subtype of breast cancer in the METABRIC study, making up about 15 per cent of the patients. It’s also a bit unusual as the tumours tend to contain very high numbers of immune cells, and their genes are much less messy than in other subtypes.

Intriguingly, many of the microRNAs found in these tumour samples had previously been implicated in controlling immune responses, suggesting that they might be playing a similar role here.

But rather than being simple switches, turning key immune system genes on and off, the microRNAs seem to be acting as genetic ‘fine-tuners’, subtly changing the activity level of important genes to make sure the immune response is just right. This is a vital function, as overzealous or underactive immune responses have big implications for health and disease, including cancer. 

What next?

So far the researchers have only looked at samples of breast cancers, so it remains to be seen if other types (or subtypes) of cancer also have characteristic microRNAs signatures, and whether they’re important. And it’s also far too soon to say how the results might shape breast cancer diagnosis or treatment, although they highlight exciting new avenues for scientists to follow.

More broadly, this is another step along the road to ever-more-detailed cataloguing of different subtypes of cancer at a microscopic level, and it’s another piece in the complex puzzle of how genes are controlled. But research like this isn’t just a molecular ‘stamp collecting’ exercise – the challenge now is to turn genetic knowledge into meaningful advances for cancer patients.

Researchers around the world are investigating the potential for using microRNAs to develop tests that could help to diagnose cancer or monitor the disease as it responds to treatment. This seems like a promising idea – microRNAs are shed from cancers into the blood and other body fluids, and are very stable, making them good candidates for such tests.

But so far it’s proved tricky to pin down individual or groups of microRNAs that reliably match up to a particular cancer type. And there’s also still a huge amount to be learned about exactly how microRNAs control gene activity, and how they fit into the complex network directing how genes are switched on and off inside cells.

It may also turn out that some of the microRNAs identified in this study could lead to new therapies for cancer – something that’s become an increasingly exciting area since the discovery that a microRNA called miR-34a can block the growth of prostate cancer cells.

And finally, this research also helps to reveal more about the underlying biology of breast cancer, enabling researchers to map out the disease in ever-greater detail. Such insights into fundamental cancer biology are crucial if we’re to make further progress in beating not just breast cancer, but all forms of cancer in the future.

Dr. Kat Arney is Science Information Manager at Cancer Research UK, the largest charitable funder of cancer research in the world, and writes for the charity’s Science Update Blog.

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