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14 November 2008
By using a rare resource developed by experts at the Welsh School of Pharmacy, UK scientists have discovered the molecular basis for tamoxifen response in breast cancer cells - and the reason why some women can develop resistance to the treatment.
Tamoxifen is given to most women for five years after they are first diagnosed with breast cancer to help stop the disease returning. However, in time some women develop resistance to the treatment, meaning their cancer is more likely to recur.
Using unique tamoxifen-resistant breast cancer cell lines developed by Cardiff scientists at the Tenovus Centre for Cancer Research, researchers at the Cancer Research UK and University of Cambridge Cambridge Research Institute have discovered for the first time the mechanism by which the breast cancer therapy tamoxifen operates. It switches off a breast cancer gene ErbB2 via a protein called Pax2. Pax2 acts as the ‘switch’ to keep ErbB2 turned off. Tamoxifen resistance occurs when ErbB2 remains switched on. The findings have just been published in full in Nature.
Breast cancer is the most common cancer in women in the UK. More than 45,500 women are diagnosed with the disease each year – 125 women a day, and the disease causes almost 12,500 deaths each year. Eight in 10 cases of breast cancer are diagnosed in women over the age of 50. It was already known that tamoxifen worked by blocking oestrogen from causing unchecked cell growth in breast cancer by switching certain genes on but the precise mechanism was unknown.
Dr Iain Hutcheson, Welsh School of Pharmacy said: "We have been developing and characterising these resistant cells for the last four years. They are an extremely rare and highly valuable resource, which we have made available to researchers throughout the world to further aid our understanding of response and resistance to antihormonal agents in breast cancer. By providing the Cambridge team with these unique cells, the team was able to reach their groundbreaking conclusions much more quickly."
Lead author Dr Jason Carroll, based at the Cambridge Research Institute, said: "We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs.
"We have discovered that for tamoxifen to work it has to block the gene ErbB2 and it does this by using a control switch that is hidden in the background of the genome, within the ErbB2 gene itself. In order for tamoxifen to be effective, this switch must be held in the off position by Pax2. Now we understand how women can develop tamoxifen resistance."
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