Identifying new approaches to the treatment of endocrine resistant breast cancer

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Breast cancer is the most common cancer that affects women. Up to 80% of patients with breast cancer have tumour cells that contain a protein, known as the estrogen receptor alpha (ER). ER mediates the effects of the hormone, estrogen and is instrumental to the growth and proliferation of breast cancer cells. When cancer affects the breast alone, it is often readily treatable. Unfortunately, when breast cancer cells spread (metastasise) to other parts of the body, the disease becomes incurable. It is believed that higher levels of ER in certain breast cancers may contribute to the risk of spread and the cancer consequently becoming incurable.Currently, most tumours that contain ER are treated with hormone treatments that reduce the levels of estrogen in the body and thereby block the actions of ER. This is often initially successful at controlling the cancer but in the case of cancer that has spread, eventually the drug stops being effective; resistance develops. At present, there are very few other treatment options available for patients when this happens - usually a different type of hormone treatment is used. This may also be effective initially but with each new anti-hormone drug used, the duration of efficacy becomes shorter and shorter. Many mechanisms for the development of resistance to these hormone treatments have been proposed. In the last 18 months, important new studies have discovered that in about 40% of patients who have breast cancer that has spread and become resistant to hormone treatment, mutations in the ER gene are present and it is believed that these mutations overcome the need of ER to be activated by estrogen and thus these cancers grow despite the estrogen reducing therapies. There is an urgent need to determine the mechanisms of action of these mutant ER proteins in the laboratory, so as to identify treatment options for patients with ER mutations. To do this, the laboratory has created metastatic breast cancer cells that have been genetically modified to gain the ER mutations. These cells recapitulate resistance to hormone treatments and so represent a very useful means of determining how the mutant proteins work and for rapid evaluation of new treatments to overcome hormone treatment resistance. In the presence of estrogen, ER can also bind with specific proteins (transcription factors) that regulate the expression of other genes. Some of these other genes regulate proteins that are responsible for the detection of hormones, bile acids and other substances (nuclear receptors) whilst others are essential to many cellular functions including metabolism and signalling (kinases). We have found that levels of some of these proteins are increased in the breast cancer cells with ER mutations. We propose that drugs that target one or more of these proteins could provide the means to treat breast cancer with ER mutations.We aim to carry out studies with the cell lines making the mutant ER proteins, to determine if any of the over-represented proteins are important for growth of these cancer cells and to test if blocking their action with specific drugs can be used to kill cells with ER mutations. Drugs that target many of these up-regulated proteins are already available and used in other clinical settings so may easily be repurposed if found to be effective. If our findings suggest that these drugs are efficacious in breast cancer cells, we would develop a clinical trial in the future to confirm these findings in patients with breast cancer. The work will be conducted by Dr Kirsty Balachandran, a specialist registrar in medical oncology who is dedicated to improving the care patients with breast cancer receive by investigating potential new treatment strategies in the laboratory and developing these to expand therapies available in clinical practice.