New discovery about how breast cancer spreads into bones

“Certain breast cancers spread to the bones using an enzyme that drills ‘seed holes’ for planting new tumours, research has shown,” The Guardian reports. The hope is drugs currently available – or possibly modified versions of them – could block the effects of this enzyme.

This largely animal and lab-based study has identified how a protein called lysyl oxidase (LOX), which some breast cancer tumours secrete, helps cancer spread to bones.

Analysis of data collected on human tumours found that in breast cancers not responsive to oestrogen, high levels of LOX production was associated with an increased risk of spread to the bones. This suggests the findings may apply to some human breast cancers as well.

Blocking the LOX protein in mice reduced the spread of cancer to the bones. Reducing the ability of the protein to create “holes” in the bone using a drug called a bisphosphonate also stopped cancer cells forming metastases in the bone.

Bisphosphonates are already used to treat osteoporosis (weakened bones) and reduce the risk of fracture in people with cancers that affect their bones. Researchers hope these drugs could also be used in people with breast cancer to reduce spread to the bone.

This will need to be tested before we can be certain that it works, but the fact these drugs are already used in humans should speed up the start of this testing process.  

Where did the story come from?

The study was carried out by researchers from the University of Copenhagen and other research centres in Denmark and the UK, including the University of Sheffield.

It was funded by Cancer Research UK, the Biotech Research and Innovation Centre, the University of Sheffield, the National Institute for Health Research Sheffield Clinical Research Facility, Breast Cancer Campaign, the Danish Cancer Society, The Lundbeck Foundation, the Velux Foundation, and the Novo Nordisk Foundation.

The study was published in the peer-reviewed journal Nature, and has been made available on a semi open-access basis – you can read it online, but you can’t print or download it.

The UK media covered this story reasonably, although their headlines don’t make it clear that such a drug would specifically be expected to stop spread to the bone and not necessarily other areas of the body.

The drug would also not be expected to have any effect on the breast tumour itself, so it would need to be combined with other treatments.  

What kind of research was this?

This was mainly a laboratory and animal study looking at how breast cancer affects the bones. Breast cancer can spread to the bone and cause the surrounding bone to be destroyed (lesions). This can cause serious complications, and the spread also makes the cancer harder to treat successfully.

The researchers wanted to investigate exactly how the breast cancer cells spread to bone and what happens within the bone when they do. They hope that by understanding this process better they may be able to find ways to stop it. This type of research is an appropriate way to study this type of question.   

What did the research involve?

Previous research suggests lower levels of oxygen within breast cancer tumours are associated with poorer outcomes for the patient. The researchers carried out a wide range of experiments to look at why this might be the case and unravel the biology behind this.

The researchers first looked at data on 344 women with information on the pattern of gene activity in their breast tumours, and also information on whether their tumours had later spread to the bone or elsewhere in the body.

They looked at whether a particular gene activity pattern that indicated low oxygen levels in the tumour was associated with tumour spread. An additional set of data from another 295 women was used to confirm the initial findings.

The researchers then looked at which proteins were secreted by breast cancer cells when they were exposed to low oxygen conditions in the lab. These proteins may play a role in helping the cancer spread by “preparing” other tissues for the cancer.

They then went on to study this protein in various experiments in mice. The mice were injected with mouse breast (mammary gland) cancer cells, which spread to the bones and other tissues.

The researchers looked at what effect increasing the levels of this protein had and what effect blocking it had on spread to the bone.

Bone is constantly being broken down and reformed by cells within it, so the researchers looked at what effect the protein had on the balance of these actions within the bone.

They also looked at the effect of a bisphosphonate drug on the formation of lesions. Bisphosphonates are drugs used to treat osteoporosis (thinning of the bones). They do this by reducing the number of bone-digesting cells, allowing the bone-building cells to take over the balance.  

What were the basic results?

The researchers found low oxygen conditions within the breast tumour were associated with cancer spread (metastases) in women with one form of breast cancer (oestrogen receptor-negative breast cancer).

It was most strongly associated with spread to the bone. This relationship was not seen in those with oestrogen receptor-positive breast cancer. 

They then looked at breast cancer cells from oestrogen receptor-negative tumours in the laboratory, including cells that had spread to bone. They found a protein called lysyl oxidase (LOX) was released in high levels in low oxygen conditions, particularly in the cells that spread to the bone.

When looking back at the data they had on breast cancer tumour gene activity and outcome, higher activity of the gene encoding LOX was found to be associated with bone metastasis in oestrogen receptor-negative breast cancer.

In mice, the researchers found cancer cells were more likely to spread to the bone and form lesions when high levels of LOX were present. Injecting the mice with cancer cells producing lower amounts of LOX, or blocking the activity of LOX with antibodies, reduced the ability of the cancer cells to form lesions in the bone.

The researchers found high levels of LOX upsets the normal balance of bone formation and “digestion”. It encourages more bone-digesting cells to form, overwhelming the action of the bone-forming cells and causing small lesions of destroyed bone to start to form. These lesions are then colonised by circulating tumour cells, allowing the formation of bone metastases.

The researchers found giving the mice with tumours a bisphosphonate stopped bone lesions forming, but did not affect the growth of the original tumour. Bisphosphonates also reduced the ability of injected cancer cells to settle in the bone and develop bone metastases if they were given to mice at the time of injection. 

How did the researchers interpret the results?

The researchers concluded they have discovered new information about the way bone metastases form from breast tumours. They say this opens up the possibility of developing new treatments for breast cancer.

They suggest that: “Bisphosphonate treatment of patients with high-LOX-expressing tumours after surgery could prevent the establishment and growth of circulating tumour cells within the bone.” 

Conclusion

This research has identified how breast tumours create conditions that allow them to spread into the bone. Most of this research was in mice, but initial experiments suggest these findings may apply in humans as well. Researchers are likely to carry out further study to confirm this.

As part of their research, researchers found a bisphosphonate – a drug that can reduce bone breakdown – was able to reduce bone metastases in mice.

These drugs are already used to treat osteoporosis and people who have advanced malignancies affecting their bone. This means that getting approval for human studies testing the effect of these drugs on the spread of breast cancer to the bone should easier than if a completely new drug was being tested.

However, we will not know for certain whether it is effective in humans until these trials are carried out. If it does work, there will still be a lot to investigate – for example, the best dose or length of treatment to use, or when best to give it.

Researchers may also try to develop alternative ways to disrupt this pathway and stop or reduce tumour spread to the bones. New treatments would require a longer time to develop and reach the human testing stage.

Such treatments would be aimed at reducing spread to the bone, but would not be expected to have any effect on the main breast tumour itself or on spread to other parts of the body, such as the brain or lungs. This means it would need to be combined with other treatments, such as chemotherapy and surgery.

This study adds another piece of knowledge to the overall picture we have of breast cancer biology, and opens up another avenue for investigation in the search for new approaches to treatment. 

Links To The Headlines

Breast cancer could be ‘stopped in its tracks’ by new technique, say scientists. The Guardian, May 28 2015

Breast cancer ‘alters bone to help it spread’. BBC News, May 28 2015

Thousands of breast cancer patients could be saved by £1 osteoporosis drug after scientists discover it stops the disease spreading to the bones. Daily Mail, May 28 2015

Scientists discover mechanism that could stop breast cancer spreading to bones. The Independent, May 27 2015

Breast cancer could be ‘stopped in tracks’ by cheap drugs. The Daily Telegraph, May 27 2015

Links To Science

Cox TR, Rumney RMH, Schoof EM, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature. Published online May 27 2105