New breast cancer ‘accelerator’ gene tracked down

Professor Carlos Caldas and his team have found a new 'accelerator' gene

Genes are the ‘instruction manual’ that tell our cells what to do, encoded within the DNA found in virtually every single cell in the body.  Some genes tell cells to start multiplying – essential for replacing dead or damaged cells – while others tell them to stop.

The ‘go’ genes are known as oncogenes and, in the same way that the accelerator in a car ramps up the speed, they drive cells to multiply when they’re needed.  But just as a stuck accelerator leads to a car speeding out of control, overactive oncogenes lead to cancer by causing cells to multiply unstoppably.

Over the years scientists around the world have discovered a number of these oncogenes, and shown that they are responsible for driving the growth of many different types of cancer. But although nearly 80 oncogenes have been identified, only around a dozen have substantial evidence linking them to the development of cancer.

Now an international team, including scientists from our Cambridge Research Institute, has added one more to this exclusive list in a new research paper published in the journal EMBO Molecular Medicine. The newcomer, known as ZNF703, is the first such oncogene to be discovered for five years, and it could lead to more effective treatments for a particularly aggressive type of breast cancer.

Watch a short video featuring Dr Kat Arney, Science Communications Manager at Cancer Research UK, explaining more about the research:

[youtube=http://www.youtube.com/watch?v=w-X432ZHicw]

On the hunt for oncogenes

The story of the search, led by Professor Carlos Caldas, starts around twenty years ago, when the scientists first began to find evidence that a region of DNA on human chromosome 8 may harbour breast cancer oncogenes.

Further experiments revealed that around a third of the breast cancer samples tested had multiple copies of this particular region, suggesting that an oncogene was highly likely to be lurking there.  In molecular terms, the region was quite large, containing a number of different genes. So the challenge was to identify the oncogene ‘needle’ in this genetic haystack.

To track it down, Professor Caldas and his team used a technique known as microarray analysis. This technology allows researchers to compare the activity levels of thousands of genes in samples from tumours and healthy tissue. In particular, the scientists focused on ‘oestrogen positive’ breast cancers – tumours that are fuelled by the female hormone oestrogen.

In total the researchers studied more than 1,100 samples of breast tumours, looking for genes in the region that were overactive or present in multiple copies in the cancers relative to healthy tissue.  Because every cancer has a slightly different pattern of genetic faults, the researchers were able to eliminate genes from their hunt one by one, checking whether individual genes were overactive in a large number of cancer samples (suggesting they might be the elusive oncogene).

Eventually they narrowed it down to two possible candidates – ZNF703 and another gene called ERLIN2.  When they studied breast cancer cells in more detail, ERLIN2 didn’t seem to be behaving like a typical oncogene, unlike ZNF703. And as the clincher, the team found two breast cancer patients in which ZNF703 was the only overactive gene, strongly suggesting that it was a new oncogene.

What about other breast cancer genes?

We’ve written before about other faulty breast cancer genes – most notably BRCA1 and BRCA2 – which are implicated in many cases of the disease. What makes ZNF703 different is that it’s an oncogene – an ‘accelerator’ gene that drives cancer when it’s overactive.

BRCA1 and 2, and many other cancer genes, are the flip-side of the coin.  They’re from a family of genes known as tumour suppressors – genes that act as the cell’s ‘brakes’ and prevent them from multiplying out of control.  When these genes are missing or underactive it’s analogous to a car’s brakes being cut, sending it careering unstoppably down the road.

It’s much harder to target tumour suppressors for treating cancer –after all, it’s difficult to develop a drug for something that’s not working.  But scientists like Professor Steve Jackson in Cambridge and Professor Alan Ashworth and his team at The Institute of Cancer Research have come up with some pretty clever solutions, such as the PARP inhibitors that we’ve mentioned several times before.

What does it mean?

The discovery puts ZNF703 in the company of only a handful of genes that have been confirmed as having a definite role in driving the growth of cancer.  The gene is now categorised as a ‘class 2 oncogene’, along with such luminaries as the snappily-named MYCVN, SKP2, RAB25 and more.  According to Professor Caldas, ZNF703 is overactive in around 1 in 12 breast cancers and could account for up to 3,500-4,000 cases per year.

The paper also highlights the importance of advances in technology.  As Professor Caldas points out:

“Scientists first discovered this region of DNA may be harbouring genes linked to the development of breast cancer twenty years ago. But it’s only with the technology we have today that we’ve been able to narrow down the search sufficiently to pinpoint the gene responsible.”

However, a lot more work will be needed to place ZNF703 in the more exclusive category of ‘class 1 oncogenes’ – overactive genes that we currently have effective drugs against.

At the moment, this group is just a trio: ERBB2 (also known as HER2), which is targeted by the drug Herceptin/trastuzumab; EGFR, targeted by drugs such as cetuximab and erlotinib; and AR (androgen receptor) – the gene that drives prostate cancer to grow in response to oestrogen – against which drugs are currently being developed.

The fact that overactive ZNF703 is so strongly linked to breast tumours – and in particular, a more aggressive type known as Luminal B breast cancer that tends to be resistant to hormone therapies such as tamoxifen – makes it a good target for future anti-cancer drugs. And it could potentially lead to the development of a test to help doctors figure out whether a woman’s cancer is likely to be resistant to hormone therapy, helping to tailor treatment more effectively to an individual patient.

As is the case with any genetic discovery of this kind, the results need to be validated in a larger number of cancer samples, followed by years of painstaking lab and clinical research before we even get close to a drug that could be available for patients.  But this discovery is a significant step along that road, and we look forward to seeing how the story unfolds in the future.

Kat

Reference:

Holland, D. et al (2011). ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium EMBO Molecular Medicine DOI: 10.1002/emmm.201100122