Scientists at NUI Galway have completed a research study funded by Breast Cancer Now that has begun to unravel why women with estrogen receptor positive breast cancer develop a resistance to endocrine treatment, and have found a potential new approach to overcome the problem.
Such findings may pave the way for new therapies to treat breast cancers resistant to endocrine therapy. The study was published this week in the international journal Oncogene by Nature Publishing Group. A cancer is called estrogen-receptor-positive if it has receptors for estrogen. This suggests that the cancer cells, like normal breast cells, may receive signals from estrogen that could promote their growth.
Every woman has estrogen and progesterone hormones in her body, which can serve as fuel for some types of breast cancer. They help the cells grow and spread. Hormone therapy, also called endocrine therapy, adds, blocks, or removes those chemicals to treat the disease.
Approximately 70% of breast cancers are positive for estrogen receptor and are treated with hormonal therapy. However, one third of breast cancer patients treated with hormonal therapy relapse within 15 years, which is why it is so important that this research continues, to help determine how the cancer finds ways to survive in these patients.
The research was performed by a team of scientists and clinicians led by Dr Sanjeev Gupta at the Lambe Institute for Translational Research at NUI Galway and lead author of the study, Dr Ananya Gupta, Lecturer of Physiology at the School of Medicine in NUI Galway. XBP1 is a protein that is involved in a cell’s response to stressful conditions, which allows tumours to grow and survive when they are deprived of nutrients.
Dr Sanjeev Gupta and his team found that XBP1 increases the production of the protein, NCOA3 that enables the breast cancer cells to avoid anti-estrogen treatment. This indicated that combining standard hormonal therapies with a XBP1 inhibitor (this blocks the XBP1 function ), could improve treatment of estrogen receptor positive breast cancer patients by preventing relapse due to therapy resistance. Dr Sanjeev Gupta, who has been working on XBP1 since 2007 says that: “This research could lead to better approaches to predict an individual patients responsiveness to endocrine therapies.”
Analysing human patient specimens, Dr Gupta and his team found that testing for high levels of XBP1 and the protein NCOA3, could predict whose breast cancer is likely to be resistant to anti-estrogen drugs and which patients could benefit most from combined treatment with hormonal therapies and a XBP1 inhibitor.
The findings suggest that resistance to anti-estrogen treatment could be overcome by targeting the cancer cells with a XBP1 inhibitor, using the cell’s reliance on XBP1 as their Achilles heel. Dr Ananya Gupta from NUI Galway and lead author of the research said: “The next step is to identify a suitable therapeutic target in the XBP1-NCOA3 pathway. XBP1 is a transcription factor, and transcription factors have been very difficult to target with small molecules. We look forward to developing new ways to target this molecule in breast cancer.”
Dr Richard Berks, Senior Research Communications Officer at Breast Cancer Now, said: “This study reveals how the XBP1 protein could be helping some breast cancers survive anti-hormone treatments. We look forward to further research to find out whether blocking this protein could reduce the risk of a patient’s breast cancer spreading or returning, ultimately helping to stop women dying from the disease. It’s crucial that we continue to find ways to make breast cancer therapies even more effective, and match individual patients with the treatments most likely to work for them.”
The study was led by NUI Galway and co-authors included Michael Kerin, Professor of Surgery at NUI Galway and Galway University Hospital (GUH ) and Director of Breast Cancer Research; and Grace Callagy, Professor of Pathology at NUI Galway and GUH. The research was funded by Breast Cancer Now, the UK’s largest breast cancer charity, created by the merger of Breakthrough Breast Cancer and Breast Cancer Campaign.