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 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 at the Patrick G Johnston Centre for Cancer Research (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.