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Dr Jason Carroll working in his lab

When a doctor suspects a woman might have breast cancer, one of the first things they do is take a small sample of cells from her breast, called a biopsy, for tests.

The cells in this tiny tissue sample carry answers to crucial questions about what happens next. First and foremost – is it cancer or not? If it is cancer, has it started spreading? And how aggressive it is likely to be?

The levels of different molecules within these cells also yield information about cancer’s nature – and in breast cancer, one of the most crucial for helping guide treatment is the oestrogen receptor (ER).

Women with high levels of this molecule in their cancer cells (called ‘ER-positive’ breast cancer) benefit from hormone therapy – drugs that either lower their oestrogen levels, or prevent cancer cells responding to the hormone. About 7 out of ten women have ER-positive breast cancer.

But there’s a second molecule – the progesterone receptor (PR) – levels of which inside breast cancer cells also seem to be important.  Doctors have known for a long time that women with high levels of both the oestrogen and progesterone receptors (‘double-positive’) have the best chance of surviving – they respond better to treatment, and their cancer is less likely to spread.

But these ‘double-positive’ women are given the same hormone therapy as those who have no progesterone receptor in their breast cancer, so doctors don’t always routinely test for this second molecule any more.

Until now, it’s been unclear why having high levels of both molecules is good news for the patient, or what benefit testing for progesterone brings.

But thanks to Cambridge-based Cancer Research UK researcher Dr Jason Carroll and his team, and their colleagues at the University of Adelaide in Australia, there are finally answers to this mystery.

Today, they’ve published surprising results of a study in the journal Nature that finally solves the puzzle of why ‘double-positive’ women do better.

And if their findings are confirmed in follow-up studies, it could make a big difference to how women are treated.

How do the ER and PR receptors work?

Only certain types of cells that respond to hormones make these receptors – for example breast, ovary and womb cells.

Both receptors are directly involved in switching genes on and off – they’re called transcription factors.

When oestrogen and progesterone are present, these hormones physically stick to their respective receptor, causing them to move into the nucleus of the cell, where DNA is housed. They can then attach to specific regions of our DNA and turn genes on or off, changing the cell’s behaviour.

When breast cancer develops, the tumour cells become overly sensitive to oestrogen. When oestrogen activates the oestrogen receptor, it turns on a panel of genes that tell the cells to keep dividing, driving tumour growth:

150707-Oestrogen-Breast-Cancer

But what happens when breast cancer cells have a working progesterone receptor too?  Dr Carroll and his team set out to find out.

The first hint

The first piece of the jigsaw fell into place when they looked at the physical relationship between the two receptors. Using ‘double-positive’ breast cancer cells grown in the lab, they made sure the cells had sufficient oestrogen and progesterone to activate both receptors, then they cracked the cells open.

When they used a sophisticated method to ‘fish out’ the progesterone receptor from the resulting mixture, they discovered something unexpected: it was physically stuck to the oestrogen receptor. This was a strong hint that progesterone – via the progesterone receptor – was somehow affecting how the oestrogen receptor works.

Using the same lab-grown breast cancer cells exposed to oestrogen only, the researchers used cutting-edge technology to pinpoint the sites in the cells’ DNA where activated oestrogen receptor attached – hence which genes it was controlling.

But when the scientists then added progesterone to the cells too, it caused a rapid shift in the points where oestrogen receptor attached to DNA.

150707-Progesterone-Breast-Cancer

At least 470 genes were controlled differently when both hormones were present compared to just oestrogen alone – the progesterone receptor was, in effect, ‘reprogramming’ the oestrogen receptor, changing the genes that it influences.

But, most crucial part was the overall effect this on the cancer cells themselves – progesterone seemed to cause the cells to stop growing as quickly.

By changing the genetic ‘programme’, the progesterone receptor was applying the brakes to the cells’ growth.

Seeing is believing

The cells used in the above experiments are based on tissue samples taken many decades ago, and kept artificially growing in a lab (called ‘cell lines’). These are a good starting point, but it was important to show this ‘ER reprogramming’ actually happens in human disease.

So the team turned a special technique developed by scientists in Professor Wayne Tilley’s laboratory at the University of Adelaide in Australia. This allowed small samples of tumour tissue to be removed from women with breast cancer and grown in the lab for a short time.

Remarkably, the team saw exactly the same effect – adding progesterone at the same time as oestrogen slowed down the rate tumours grew.

They also saw exactly the same phenomenon in mice transplanted with human breast cancer cells: oestrogen fuelled tumours’ growth, but progesterone put the brakes back on.

The final, and most crucial, experiment was to see if their findings had any potential implications for treating breast cancer.  Again working with mice transplanted with tumour samples and given oestrogen, the researchers used the standard treatment for hormone-responsive breast cancer – tamoxifen, which slowed down tumour growth.

But when they gave the mice tamoxifen AND progesterone, the tumours grew even more slowly.

Changing the way breast cancer is treated?

Dr Carroll’s research is a big step forward in understanding the role of progesterone receptor in breast cancer. Until now, its presence was simply considered an indication of how good a woman’s chances of surviving were.

But Dr Carroll’s study findings reveal that the receptor itself is the direct reason why these women have a better outlook.

Understanding the progesterone receptor’s role as a molecular handbrake on oestrogen-fuelled growth could also explain the observation that breast cancers frequently evolve to get rid of their progesterone receptors – this is an advantage to cancer, helping it grow quicker.

This new research offers a unique opportunity to exploit the braking action of the receptor with hormone therapy to improve breast cancer outcomes. According to Dr Carroll, this is precisely what needs to be done, and the next steps are obvious.

“The results are pretty clear and potentially have direct benefits for many women with breast cancer,” he told us.

“We’re already discussing a clinical trial to test whether giving women with ER/PR double-positive breast cancer progesterone, alongside oestrogen-blocking drugs, helps more women survive this disease”.

If proven successful, they suggest that it could benefit up to half of women diagnosed with the disease.

It’s even possible that Professor Tilley’s new technique of growing tumour tissue samples in the lab could form the basis of a test to help doctors identify who might benefit from this combination of treatments.

“The pioneering technology we used in this study could be used as a simple way to see if adding progesterone to oestrogen blocking drugs further slows tumour growth,” Tilley predicts.

This potential new dual therapy is still a way off – there’s a lot of clinical research ahead before we know for sure that giving progesterone to women with ‘double-positive’ breast cancer will definitely help them.

But it’s an elegant and exciting demonstration of how hard graft in laboratories around the world is continuing to make strides against a disease that – despite undoubted progress – still claims the lives of nearly 12,000 UK women each year.

– Emma

[Note: In the light of media coverage of this story this morning, we want to clear up an important point: the effects observed in this study were from using progesterone itself. Many contraceptives, and certain forms of HRT, contain derivatives of progesterone (e.g. medroxyprogesterone acetate, MPA) – these seem to act differently. So headlines claiming that a hormone ‘found in The Pill slows growth of tumours’ are slightly inaccurate.]

Reference

Mohammed H. et al. Progesterone receptor modulates estrogen receptor-α action in breast cancer, Nature (2015), DOI: 10.1038/nature14583

Comments

Emma Smith November 26, 2015

Really sorry to hear about your breast cancer diagnosis Ritika. Dr Carroll’s research showed that progesterone could actually help slow the growth of breast cancer, but it’s early days yet. If you have questions about your treatment, you can call our cancer information nurses, Monday to Friday 9-5 on 0808 800 4040.
Emma

Ritika November 25, 2015

Hi…I was diagonosed with ER – PR+ Breast cancer 2 yrs back. How effective is tamoxifen in such case as what I would really need is something to stop progesterone from going wrong?

Emma November 13, 2015

Hi Susan,
We’re really sorry to hear about your breast cancer diagnosis. The research described in this article shows that progesterone slows the growth of double positive breast cancers in mice, but we are still a way off knowing if the same is true in women with breast cancer. Furthermore, there’s also no information on how creams might compare to other ways of taking progesterone. Until we know more, we recommend you talk to your doctor before using any hormone treatments. You can also call our cancer information nurses, Monday to Friday 9-5 on 0808 800 4040.

Susan November 12, 2015

I have just been diagnosed with an ER/PR positive receptors breast tumour and found your research article interesting. I have used natural, compounded by a pharmacist, progesterone cream for a number of years to control unbearable body soaking hot flashes (I did not want to use HRT due to obvious concerns). The cream eventually evened out my postmenopausal “heat flashing” problems, so much so that I had planned to remain on the small amount I use each day (with a 7 day break).
Now, after my diagnosis, I stopped using the cream a couple of weeks ago afraid that somehow this cream may have been involved. However, could the reverse be true….that the natural progesterone cream was actually giving the PR receptor the ability to fight the ER cells from being able to speed up their growth.
Could this also go along with the research that looked at the fact that premenopausal women who had breast surgery at the point when their own progesterone was high faired better as far as recurrences were concerned?
Perhaps there is a case for my staying on the natural progesterone cream?

Emma October 9, 2015

Hi Nina,
Sorry for the slow reply. You’ve made some really good points, thank you for sharing them with us.

Dr Carroll’s research is really interesting, but it was only carried out in cells grown in the lab and in mice. There’s no evidence yet that giving progesterone to women with double positive breast cancer alongside tamoxifen would be more effective, or reduce side effects. We need clinical trials to determine if it would benefit patients, and if so, how best to give progesterone (tablets or an intrauterine device) and whether it affects the risk of developing other types of cancer in the long term. But early research like Dr Carroll’s is crucial, as it provides the groundwork and rationale doctors need to set up clinical trials to test new treatments.

We also need more good, large scale studies to better understand the wider effects of different types of hormonal treatments and devices, alone and in combination, including their effects on cancer risk. These types of studies are usually complex, and involve large numbers of women being monitored over long periods of time, so they are challenging for researchers to carry out. We continue to support this type of ‘population research’ though, for example the Million Women Study http://www.millionwomenstudy.org/introduction/, which (among other things) is looking into how HRT and the Pill affect women’s risk of cancer.

Emma

Nina October 2, 2015

Thank you for this summary, Emma. This research raises further questions, as all research does. The study authors do not make recommendations for practical application of their work. Questions include:
[1] Should progestagens be added to hormonal treatment after breast cancer? This of course needs to be researched in larger studies.
[2] Tamoxifen increases the risk of endometrial cancer. Does adding progestagens prevent endometrial cancer in women who are taking tamoxifen? Would adding progestagens allow for increased length of use of tamoxifen, i.e. more than 10 years, since the endometrium is now protected? If so, tamoxifen + progestagens could become a lifelong treatment, like aspirin after heart attack or stroke.
[3] Should women on tamoxifen be offered a Mirena coil to protect their endometrium? One of the most important side effects of tamoxifen is the increased risk of endometrial cancer. A Mirena coil is likely to protect the endometrium, as it does women on HRT.
[4] Do we need to review combined oestrogen + progestagen HRT? Progesterones in HRT are used to protect the uterus, but increase breast cancer risk. A Mirena coil could protect the endometrium while the dose is so small as to be much less likely to increase the breast cancer risk than oral progestagens.
What are the experts’ views on this? I would love to see learned views on these issues on this blog.

Alan De Vendra August 17, 2015

The binding and location of the oestrogen together with the progesterone described in these findings is huge in it’s own right.
If what I am reading is correct it places an emphasis on the usage of oestrogen together with progesterone for more successful post menopausal hormone replacement therapy with a lower risk potential of cancer.
Clarification of this area of these findings are important for millions of postmenopausal women world wide.

becksina9 August 15, 2015

after surviving cancer through mastectomy i was given Tamoxifen too much or too soon im not sure but i was just recovering from cancer took tamoxifen it made my womb swell up and i had to have an emergency hysterectomy nearly bled to death.Its obvviously not suitable for everyone and i think my body wasnt ready for it had enough to do just surviving and resting.After having everything taken away womb cervix ovaries i recovered and am now still well 20 years later.

Helen Gould August 14, 2015

I found this article fascinating, especially as I have already had a conversation with my doctor regarding the risk of developing breast cancer whilst using HRT – I am post-menopausal, but had 4 miscarriages before my son was born, and when my hormones were tracked, they revealed a 24-day cycle where progesterone, follicle-stimulating hormone and luteinising hormone were deficient, whilst oestrogen was relatively normal. The question I asked my doctor was, if you were exposed to oestrogen more often because of a short cycle, does that put you at higher risk of breast cancer? He said it was a very good question, but couldn’t answer it. I don’t know if any of this sheds any light on the problems you’re investigating, but I have wondered about this so often that I felt it was important for me to send this comment.

Sue Gregory August 14, 2015

It seems inadequate but thank you researchers.

Melanie Taylor August 13, 2015

Very interesting, thanks for all your hard work! My own tumour was Oestrogen 8; Progesterone 7, and I took Tamoxifen. Maybe one reason why I am still fighting fit, 8 years down the line :-)

Jackie Cowling August 6, 2015

Thank you ! Dr Carroll and your team. I am a nurse and terrified of this disease as I am high risk . I hope it feels as rewarding to you all to help more women feel reassured and hopeful .

Emma July 9, 2015

Hi Rosemary,
Just to clarify, the research was all carried out in the lab, on breast cancer cells and in mice. The results provide good evidence for opening a clinical trial to test this approach in women, and doctors are discussing this now. But there is no trial open now or in the immediate future (trials can take a year or more to set up), nor detail on what treatments women would be given.
Emma

Chrissie July 8, 2015

For many decades naturopathic doctors have been extolling the virtues of progesterone whilst the NHS recommend this only as protection against ovarian cancers. Perhaps now it’ll catch up?

Charlotte July 8, 2015

Very interesting findings from Dr Carroll and team

rosemary Lambert July 8, 2015

I note that tamoxifen was mentioned. As I’m post menopausal I’m on letrozle . Is this trial applicable ?