Breast cancer survival is one of the big success stories of recent years. Thanks to improvements in screening and treatment more than 70 per cent of women now survive for more than ten years, compared to around 40 per cent back in the 1970s.
But while this is cause for celebration, the statistics hide the fact that most of this progress has been made in treating breast cancers driven by the female sex hormone oestrogen.
So-called oestrogen-receptor positive (ER-positive) breast cancer accounts for around two-thirds of cases, and can usually be treated with hormone therapies that block the production or action of oestrogen – notably drugs such as tamoxifen and aromatase inhibitors.
Unfortunately, these drugs don’t work in women whose breast cancers lack oestrogen receptors (ER-negative), so alternative chemotherapy options are used. These are often not as successful as hormone therapy, and new treatment approaches are urgently needed.
Now a paper from Cancer Research UK scientists, published in the EMBO Journal this week, shines the spotlight on a subset of these ER-negative breast cancers – known as molecular apocrine breast cancer - showing that they may be fuelled by a molecule more commonly implicated in prostate cancer.
Not only do the results help to explain the puzzle underpinning the disease, but they bring hope for more effective treatments in the near future.
From oestrogen to androgen
Women’s bodies are awash with female hormones – namely oestrogen and progesterone – but they also produce a small amount of testosterone, more commonly thought of as a male hormone.
These hormones act by entering cells and attaching to receptors – the oestrogen, progesterone and androgen (testosterone) receptors, respectively – which then switch on specific genes causing the cell to do certain things (for example, grow and divide).
Scientists have known about the roles of the oestrogen and progesterone receptors in breast cancer for some time, showing that they are a key force in driving cancer cells to divide in response to hormones. But, curiously enough, most breast cancers also contain androgen receptors.
In oestrogen-positive breast cancer, androgen receptors have been found to counteract the effects of oestrogen, slowing down cancer growth. This is borne out by research showing that women whose breast tumours carry both oestrogen and androgen receptors are likely to respond better to treatment and survive longer.
But nobody knew what androgen receptors were doing in breast cancers that didn’t have oestrogen receptors. So a team of researchers from our Cambridge Research Institute – led by Dr Jason Carroll and Dr Ian Mills – along with colleagues in Norway and Australia, set about finding out.
Studying the switches
Hormone receptors act as molecular ‘switches’, attaching to special regions of DNA and turning specific genes on.
To find out what the androgen receptor was up to, the researchers studied three different cell lines – human cancer cells grown in the lab. These were breast cancer cells lacking oestrogen receptors but containing androgen receptors (similar to molecular apocrine ER-negative breast cancer), breast cancer cells with both receptors (similar to ER-positive breast cancer), and prostate cancer cells (which only carry the androgen receptor).
Using various techniques, the scientists looked at the cells’ DNA to find out which genes the androgen and oestrogen receptors were attached to (and therefore switching on) in the different types of cells – and got a rather surprising result.
Rather than finding that the oestrogen and androgen receptors were turning on different genes, they noticed a significant overlap. Around half of the locations occupied by oestrogen receptors in the ER-positive breast cancer cells were hogged by androgen receptors in the ER-negative cells, presumably switching on the same genes that drive cancer growth.
This poses an interesting question. Oestrogen and androgen receptors each have unique shapes, which match different regions of DNA, like keys fitting into locks. In theory, the androgen receptors shouldn’t even be able to attach to the oestrogen receptor sites, let alone switch on genes.
So how were they managing it?
The missing link
The missing piece in the puzzle came in the form of a protein called FoxA1. Like the androgen and oestrogen receptors, FoxA1 sits on DNA and helps to switch genes on by ‘opening up’ the DNA so genes can be read. It’s well-known to scientists, as it helps oestrogen receptors to turn on genes in breast cancer cells, but was only thought to be important in oestrogen-receptor positive tumours.
However, when the Cambridge team looked at the location of FoxA1 on DNA in the ER-negative breast cancer cells, they found an almost exact match with the androgen receptors – more than 98 per cent of the sites occupied by androgen receptors also attracted FoxA1. In contrast, only half of the sites occupied by oestrogen receptors in AR+ ER+ cells were targets for FoxA1.
This told the researchers that FoxA1 must be acting as a ‘skeleton key’, allowing androgen receptors to hijack sites normally reserved for oestrogen receptors and switch on genes driving cancer growth.
What does this mean for treating breast cancer?
This is the first time that researchers have shown that androgen receptors play an important role in switching on ‘oestrogen responsive’ genes in breast cancer cells that don’t carry oestrogen receptors.
And unlike the situation in breast cancers with both types of receptor – where the androgen receptor acts as a ‘brake’ on cancer growth – it’s likely that androgen receptors are responsible for fuelling the growth of ER-negative cancer cells in molecular apocrine cancers.
This research opens up two avenues for exploration that could lead to new treatments for molecular apocrine ER-negative breast cancer. Firstly, it suggests that drugs targeting FoxA1 may be useful for treating the disease – an approach that is already being explored but is yet to bear fruit.
Perhaps more importantly, the findings also suggest that anti-androgen drugs could be useful for treating women with this particular type of breast cancer. These drugs are currently used to treat men with prostate cancer – a disease fuelled by testosterone acting on androgen receptors.
Given that anti-androgens such as bicalutamide are used to treat thousands of men safely every year, it should be relatively quick to test this idea in a clinical trial.
This work is still at an early stage, and it’s important not to extrapolate too far from cell lines growing in the lab to real women living with ER-negative breast cancer. But this discovery is a big step towards making a success story out of this type of breast cancer too.
Robinson J et al (2011). Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1 EMBO Journal DOI:10.1038/emboj.2011.216