Oxygen-response protein increases risk of breast cancer spreading to the lung

A protein that is made during a short-term drop in oxygen levels in the lungs could make breast cancer more likely to spread there, new research led by Queen's University suggests.

In a study funded by Breast Cancer Now, researchers found proteins made in blood vessels that can help breast cancer to spread to the lungs, while also identifying others that could help stop the disease from spreading here.

Researchers led by Dr Cristina Branco, a Breast Cancer Now Fellow and lecturer from The Patrick G Johnston Centre for Cancer Research at Queen’s University Belfast, found that an increase in the protein HIF-1α can physically alter the structure of the capillaries (the smallest blood vessels)* in the lungs of mice.

These changes make it easier for cancer cells to move from the bloodstream into the lung, and to grow into secondary tumours. Meanwhile researchers found the production of a similar protein, HIF-2a, to have a protective effect.

Both of these proteins are known to be involved with regulating a cell’s energy levels and the abundance of each of these proteins changes in response to oxygen levels in the lungs1. Short-term (up to 24 hours) low levels of oxygen, such as what occurs in conditions including pulmonary hypertension,** anaemia,** and sleep apnoea** usually lead to an increase in HIF-1α.

The role of HIF-1a in cancer cells is already known to make the disease more aggressive. In this study, researchers show that the levels of this protein in non-cancer cells can also aid the disease spreading. This is important for two reasons: cancer cells need normal cells to survive, and use blood vessels to travel and invade organs other than the breast, so it is useful to study how non-cancer cells behave during the spread of cancer.

When breast cancer spreads to another part of the body, it is known as secondary (or metastatic) breast cancer. While it is possible to treat secondary breast cancer for some time, it currently cannot be cured. The aim of treatment for secondary breast cancer is to control and slow down the spread of disease, try and relieve the symptoms, and support people to ensure they have the best quality of life possible while living with the disease.

The lung is a common site for breast cancer to spread to and when it does, it causes symptoms such as breathlessness and a persistent cough, both of which can significantly affect a person’s quality of life.

To spread to another part of the body, cancer cells that detach from the primary tumour in the breast need to enter the bloodstream and, importantly, escape from the blood vessels at different organs, where they can enter the surrounding tissue. A better understanding of the factors that influence the stability of blood vessels in certain organs could help researchers develop new ways to stop breast cancer spreading around the body.

The small blood vessels in the lungs are especially sensitive to changes in oxygen levels and respond by altering the levels of HIF-1α and HIF-2α proteins. This study looked at how changes in the levels of these two proteins in cells that line the walls of these blood vessels can alter the susceptibility of the lung to secondary tumours, and the mechanism behind this.

Researchers used low oxygen conditions to model changes in HIF protein levels in the lung. Lower oxygen conditions were applied for either 24 hours (to increase HIF-1a protein) or 10 days (to increase HIF-2a) and scientists then looked to see if there was a difference in the number of tumours that had formed in the lungs in mice.

The group found that more tumours formed in the lungs when there were higher levels of HIF-1α present in capillary cells, however when there was an increased level of HIF-2a present, less tumours developed. This suggests that the presence of high levels of HIF-1α in these specific blood vessels helps breast cancer to spread to this organ.

The mice with higher levels of the protein HIF-2α in the same cells developed less tumours in the lungs, suggesting that higher level of HIF-2α here has a protective effect.

Experts hope these findings could be used in the future to develop strategies to help protect the lungs from secondary breast cancer, including identifying patients at greater risk of their disease spreading, and establish whether other organs that breast cancer tends to spread to, such as the brain or liver, may be affected by similar changes. This could help anticipate the organs at the highest risk.

Further research to understand how HIF-1α impacts the spread of breast cancer could lead to new drugs being developed that may disrupt this process. This understanding could also potentially lead to HIF-1α being used as a marker to identify susceptible organs, and help us to understand whether health conditions that lead to either changes in oxygen levels or HIF-1a accumulation, such as inflammation or other underlying conditions, may affect an individual’s risk of developing secondary breast cancer.

Lead author Dr Cristina Branco, said: “One of the main challenges for patients and clinicians alike is that it is hard to predict, based on the diagnosis alone, which patients will develop secondary breast cancer. My team and I believe that research such as this, which involves studying the patient alongside studying the disease, will help to identify the patients most at risk, as well as why they are most at risk.

“In the future, I hope that our research into understanding the molecular factors and mechanisms that facilitate or delay secondary tumours will lead to the development of treatments that can help prevent or better treat these patients.”

Dr Simon Vincent, Director of Research, Support and Influencing at Breast Cancer Now, which funded the study, said: “This exciting research gives new insight into the impact that proteins produced by healthy cells have on the spread of breast cancer, which could help us to protect certain organs, such as the lungs, from secondary tumours. In the future, it could be possible to identify individuals who are at higher risk of their breast cancer spreading to the lungs by looking at the levels of HIF-1a or HIF-2a protein.

“Once breast cancer has spread, while it can be treated for some time, it currently can’t be cured. With around 11,500 women and about 85 men still dying from breast cancer each year in the UK, we urgently need to find new ways to prevent the disease spreading and to treat it more effectively when it does. We look forward to further research that could use this knowledge to develop new treatments to protect the organs that are most at risk of secondary breast cancer, helping stop the spread of disease.

“In the meantime, anyone who is living with secondary breast cancer or concerned about the spread of their breast cancer can call our free Helpline on 0808 800 6000. Our expert nurses are just at the other end of the phone.”

This study was funded by Breast Cancer Now, with support from Cancer Research UK Cambridge Cancer Centre which funded PhD student Moritz Reiterer.

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