It’s sometimes easy to forget how clever breast cancer can be. Despite many advances in treatment, some breast cancers still find ways to become resistant to drugs and grow back. To stop people dying from the disease, we need to find all of breast cancer’s escape routes – and block them.
In research published today, scientists funded by Breast Cancer Now have uncovered another escape route – cancers that normally depend on hormones to grow could instead be switching to molecules made from cholesterol. But first, let’s look at what these breast cancers are trying to escape from.
Anti-hormone treatments
Anti-hormone drugs are targeted treatments for ‘ER-positive’ breast cancer, the most common form of the disease which represents up to 80% of cases. In these cancers, the hormone oestrogen attaches to the oestrogen receptor (ER) which in turn stimulates the growth of breast tumours. All anti-hormone treatments aim to prevent this interaction between oestrogen and the ER, but they work in different ways.
Drugs called aromatase inhibitors, which include anastrozole (Arimidex) and letrozole (Femara), stop the production of oestrogen, removing the fuel that these breast cancers need to grow. Tamoxifen blocks the oestrogen receptor, preventing oestrogen from activating it and driving breast cancer growth. Finally, a drug called fulvestrant (Faslodex) destroys the ER, meaning oestrogen can’t fuel the cancer anymore. Anti-hormone treatments like these have helped improve survival for thousands of patients and continue to save lives every year.
However, despite the treatments available, up to around 30% of ER positive patients see their breast cancer come back. Our researchers have been investigating one of the ways they do this: exploiting the machinery that our cells use to make their own cholesterol.
Cholesterol – the good and the bad
Although too much cholesterol can be damaging to our health, it is still essential for our cells and our bodies to function. For example, it is one of the main components of cell membranes (the barrier that lines all cells), and is also the raw material to make a range of different hormones, including oestrogen and testosterone.
To keep up with demand, cells have a process called the ‘cholesterol biosynthesis pathway’ – a process that manufactures most of the cholesterol we need. But as is often the case in cancer, it appears that this normal process could be hijacked for the benefit of breast tumours.
A new escape route
A team lead by Dr Lesley Ann Martin, based at the Breast Cancer Now Toby Robins Research Centre in London, published research today which found that ER positive breast cancer cells can continue to grow in the lab without oestrogen by using a molecule made from cholesterol called ‘25 hydroxycholesterol’.
This molecule, which is produced by the cholesterol biosynthesis pathway, can mimic the effect of oestrogen by attaching to ER, causing it to stimulate the growth of breast cancer cells – allowing breast cancer cells to multiply in the absence of oestrogen such as when they are treated with aromatase inhibitors.
Now that we know more about how some breast cancers might escape anti-hormone treatments, what comes next? Dr Martin believes this discovery has two main implications.
Helping to tailor treatments
Firstly, this could one day help doctors predict whether a patient’s tumour might become resistant to aromatase inhibitors, by measuring the levels of 25-hydroxycholesterol or proteins involved in the cholesterol biosynthesis pathway in a tumour. If likely to develop resistance, patients could be switched to alternative anti-hormone drugs.
In fact Dr Martin’s team has shown that this might be possible, by studying tumours from patients who were treated with anti-hormone therapies. Looking at the genes which make proteins in the cholesterol biosynthesis pathway, they found that some of these genes are more active in the tumours which are associated with poor response to anti-hormone treatment. More work needs to be done to confirm this, but it’s a promising start.
Statins for breast cancer – an intriguing possibility?
The second potential outcome of today’s research, and one that has received a lot of attention in the media, is the suggestion that cholesterol-blocking drugs known as statins could potentially help to treat ER-positive breast cancer. Statins effectively shut down the cholesterol biosynthesis pathway, which in theory could reduce the production of 25-hydroxycholesterol and so cut off this alternative fuel supply for ER-positive breast cancer.
Statins are already widely used to treat people with high cholesterol, and help to reduce the risk of heart attacks and stroke. There is already some evidence to support the idea of treating breast cancer with statins, and Dr Martin is not alone in believing that it is high time for a clinical trial which definitively tests whether statins improve the chances of survival for people with ER-positive breast cancer.
Though it’s still early days for this research, ultimately it’s another positive step towards a future where we can outsmart ER-positive breast cancer, and tailor treatment for each individual with the disease – which will help us achieve our ambition to stop people dying of the disease once and for all.