Prostate cancer and oestrogen – another piece of the jigsaw?

While oestrogen is best known as a female sex hormone, men produce it too – albeit in lower amounts. And there’s emerging evidence that oestrogen might be involved in the growth of prostate cancer – particularly fast-growing, aggressive prostate cancers.

As we wrote in February, there are some pretty big gaps in our knowledge about this disease – particularly what causes it, who’s most likely to get it, and, importantly, why some prostate cancers grow much faster than others.

A lot of previous research has focused on ‘androgens’ – male sex hormones like testosterone. And these certainly fuel prostate cancer growth. So prostate cancer is often treated by blocking their action, although tumours frequently become resistant to this treatment.

But there’s a growing stack of circumstantial evidence that oestrogen is also involved.

The latest research suggesting it might play a role was published in May, in the Journal of the National Cancer Institute, and looked at ‘oestrogen signalling’ in prostate cancer samples. We’ll look at the paper in a minute, but first, some background…

Oestrogen signalling

Oestrogen’s a hormone – a chemical messenger that changes the behaviour of cells by entering them and binding to one or more proteins – ‘oestrogen receptors‘ or ERs – which then become activated.

To make matters slightly confusing, there are actually two forms of oestrogen receptor – ERα and ERβ – and these are produced in different amounts in different cell types.

Both receptors act in similar ways – they turn off particular genes, and turn others on, creating a cascade that ‘reprograms’ the cell and tells it to do something new – usually to ‘go forth and multiply’. But they work differently in different types of cell.

The cells of the female sex organs are particularly oestrogen-sensitive – as readers of the fairer sex will be all too aware. So cancers of these parts of the body often ‘hijack’ the oestrogen receptor for their own ends – notably breast cancers, which often produce large amounts of the oestrogen receptor.

Thankfully, drugs designed to block oestrogen signalling, like tamoxifen or anastrozole, have proven to be extremely effective treatments for oestrogen-positive breast cancer, and survival times have significantly increased since their widespread use.

But what’s all this got to do with prostate cancer?

Two years ago, a team in the US led by Professor Mark Rubin discovered a specific gene defect in about half of all prostate cancers. The nature of the defect was particularly interesting, as it joined the promoter region – the ‘on/off switch’ – from a gene called TMPRSS2, to the ‘business-end’ of another gene called ERG.

To make a crude analogy, this is the biological equivalent of wiring your door-bell to your central heating. Normal everyday actions start to have bizarre, and potentially dangerous, effects.

Now, this sort of gene fusion is thought to be pretty common in cancer cells, which have grossly abnormal DNA that often looks like it’s been through a molecular mangle. But to find a specific fault like this in nearly half of all samples was very interesting – this suggested that it plays an important role in the disease’s progression.

Sure enough, the team found that the samples containing the TMPRSS2:ERG fusion came from men with advanced, aggressive tumours. So they set about studying what exactly this weird chimera was doing.

The TMPRSS2:ERG gene fusion is activated by oestrogen

To do this the team, used state-of-the-art technology to analyse the activity status of over 6,100 separate genes in more than 450 prostate cancer samples, many of which were known to containTMPRSS2:ERG.

What they found was striking. There was a distinct set of genes that was almost always turned on in cancers containing TMPRSS2:ERG, amounting to a ‘signature’ for the gene’s activity.

So they compared this signature to other known gene signatures… and found that it looked just like what you’d expect to see if oestrogen signalling was occurring.

This suggested that oestrogen, via the oestrogen receptor, activatesTMPRSS2:ERG – which then tells the cancer cells to multiply.

To confirm this, they treated prostate cancer cells with a variety of different oestrogen-like chemicals, each of which had a different effect on the two oestrogen receptors, α and β, we mentioned earlier.

To cut a long story short, they found that TMPRSS2:ERG – this abnormal gene that’s involved in half of all prostate cancers, cancers that tend to be aggressive and spread – seems to be able to be switched off by chemicals that turn on ERβ and turn off ERα. And switching offTMPRSS2:ERG seems to stop prostate cancer cells in their tracks – at least in the lab.

This suggests that we could find an oestrogen blocker to combat aggressive prostate cancer and offer hope to tens of thousands of men worldwide, just as we’ve done for breast cancer.

But this research also has wider implications…

It suggests why prostate cancers become resistant to androgen-blocking therapy – although they’ve lost the ‘go forth and multiply’ signals from the androgen receptor, they can still be encouraged to grow by the oestrogen receptor.

It also possibly squares an intriguing circle. It has often been observed that rates of aggressive prostate cancer are higher in overweight and obese men, and that these men are more likely to die from their cancer. We already know that fat cells make oestrogen, so it may be that high levels of oestrogen in the bloodstream of overweight men encourage their cancers to grow faster by ramping up the activity of TMPRSS2:ERG.

What the research doesn’t suggest – immediately – is that oestrogen, or oestrogen-like chemicals, cause prostate cancer. We’re well aware of the anxieties people have about ‘hormones in the environment’ – and we’ll be writing about this soon – but this research looks at how existing prostate cancers grow, not how they arise in the first place.

Nevertheless, work like this is opening up all sorts of avenues to look at oestrogen’s involvement in prostate cancer, and how its signalling pathways might help us develop new treatments.

We’ll be keeping a close eye on this field, as there are all sorts of other tentative connections between oestrogen and prostate cancer that might be explained by further studies.

Watch this space.

Henry