Oestrogen causes DNA mutations – is this how it fuels cancer?

Oestrogen can lead to mutations in DNA, according to new research by Cancer Research UK scientists

The evidence that the sex hormone oestrogen is involved in cancer is overwhelming.

For example, breast cancer is more common among women who take HRT and the Pill for long periods, both of which add oestrogen to the body’s natural levels. And this most common of cancers is intimately linked to levels of the hormone over a woman’s life.

Oestrogen is also involved in cancers of the womb and ovaries, and, potentially, prostate cancer.

But we understand little about exactly how oestrogen affects the internal chemistry of our cells so that they become more likely to divide out of control. Several theories have been put forward, but scientists are still working hard to figure this out.

Some think that oestrogen encourages certain cell types to divide more often, and that the increase in cancer risk can be explained by the simple fact that more cell divisions means a greater likelihood of cancer-causing mistakes being made.

Others think that oestrogen turns on certain genes inside cells at the wrong time, and that this encourages cancer – for example, by preventing damaged cells from dying.

And finally, there’s laboratory evidence that oestrogen can directly bind to, and damage, DNA – although quite whether this occurs in real life, is far from clear.

But new research published today by Cancer Research UK scientists, with support from a team in Spain, adds a new theory to the mix – one that’s as least as strong as the others. And intriguingly, their research points the finger at the immune system, the body’s in-built self-defence mechanism.

Mutations in the immune system – a force for good

From comic books to cancer, the word ‘mutant’ has negative connotations.  Mutations are mistakes or variations in the genes in our cells that can be passed on as cells divide. And cancer is thought to develop when a single cell picks up mutations that cause it to grow out of control.

But mutation can be a force for good too – its how our immune system generates the extraordinary diversity needed to fight the thousands of different invaders it will encounter over our lifetime. And an important step in this is a process called ‘somatic hypermutation‘.

B-cells are antibody factories

Our blood contains specialised white blood cells called B-cells. Their job is to take samples of foreign ‘nasties’ – like bacteria and viruses – floating around the body. The B-cells then become ‘activated’, and make antibodies that bind to the specific bit of the bug they’ve encountered. They then release millions of these antibodies into the bloodstream to mop up and neutralise any remaining invaders.

Although exactly how this activation occurs is still the subject of much research, it’s clear that a key player is an enzyme called Activation-Induced Deaminase, or AID, which is manufactured inside B-cells just after they’ve encountered a new invader.

AID causes somatic hypermutation – a process which chemically changes B-cells’ antibody genes to contain hundreds of new mutations. This allows the body’s B-cells to produce a whole slew of new antibodies. A subsequent process of elimination then selects the right antibody for a given invader, from the population of activated B-cells.

What’s this got to do with oestrogen?

The first clue that oestrogen might help regulate our immune system came from two observations. Firstly, women often have faster immune responses than men.

Secondly, it has been known for some time that certain autoimmune diseases were more common amongst women than men. This hinted that something about ‘being female’ might cause a person’s immune system to be more active.

Enter Dr Svend Petersen-Mahrt at Cancer Research UK’s Clare Hall laboratories, who’s been studying AID’s role in cancer for some time. His team set out to investigate whether this enzyme might explain the differences between men’s and women’s immune systems.

First, working with B-cells isolated from the pancreases of mice, they showed that oestrogen switched AID on, and that another hormone called progesterone could switch it back off.

Oestrogen activates AID and causes DNA mutations (click to enlarge)

They then showed that the AID gene contains a tiny switch, known as an ‘Oestrogen Response Element’. Oestrogen flips this switch so cells produce more AID enzyme, which in turn, increases the number of mutations in antibody genes (see diagram).

But what about cancer?

So oestrogen helps to regulate the immune system. But recently, other scientists have found that AID can cause a specific, cancer-causing mutation to occur, called a c-myc/IgH translocation, known to be involved in Burkitt’s lymphoma – a cancer of the immune system. When the Cancer Research UK team tested B-cells for this, they found that it occurred more often in B-cells that had been exposed to oestrogen.

But the phenomenon was much more widespread than they expected. AID was mutating other genes in B-cells – including one, CD95/Fas, known to be involved in cancer.

Finally, and critically for this story, the team showed that AID wasn’t just being activated in B-cells. In almost every cell and tissue type they looked at, including egg cells, breast tissue, ovarian tissue, prostate cells and T-cells, exposure to oestrogen led to the production of more AID enzyme.

(It’s worth noting, though, that the team didn’t test these cells or tissues for actual DNA alterations – this is important, and we’ll come back to it later).

What does this mean?

This research has established that there is a clear way that oestrogen can lead to DNA mutations. This is entirely new to science, and is a discovery that is almost certain to have important implications for future cancer research.

If you wanted to be critical, you might point out that that this paper stops short of the killer piece of evidence – whether this pathway is involved in human cancers ‘in real life’.

And although the researchers proved that oestrogen can switch on AID and cause mutations in B-cells, the team haven’t yet shown that oestrogen causes AID to make cancer-related mutations in non-immune cells – this is their next objective.

But despite this caveat, it’s fair to say that the circumstantial evidence that AID plays an important role in cancer is beginning to stack up. For example, a Japanese team have shown, in a 2007 paper in Nature Medicine, that AID could play a role in stomach cancer, and also how chronic inflammation of the liver might activate AID and cause liver cancer.

Clearly, there’s more to discover about how this essential defence mechanism is involved in the disease – and this paper has set the scene for a deeper look at how oestrogen, and AID, work at a fundamental level. Dr Petersen-Mahrt’s pioneering work could one day lead to the development of drugs or other treatments to prevent oestrogen-linked cancers from developing.

Henry

Listen to Dr Petersen-Mahrt talk about the significance of his work (mp3)

Reference:

Siim Pauklin, Isora V. Sernández, Gudrun Bachmann, Almudena R. Ramiro, Svend K. Petersen-Mahrt (2009). Estrogen directly activates AID transcription and function
The Journal of Experimental Medicine