Tamoxifen resistance unravelled

18 Nov 2008

Scientists crack the code to tamoxifen resistance

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, according to a study published in Nature.

Tamoxifen is given to most women for five years after they are first diagnosed with breast cancer to help prevent the disease from coming back but some women develop resistance to the treatment after time, meaning their cancer is more likely to return.

Researchers at the Cancer Research UK 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 a 'switch' to keep ErbB2 switched off. Tamoxifen resistance occurs when ErbB2 remains switched on.

Previously it was known that tamoxifen worked by blocking oestrogen from causing unchecked cell growth in breast cancer by switching certain genes on but the mechanism by which this occurred was unknown.

Lead author, Dr Jason Carroll 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."

The production of oestrogen can cause breast cancer cells to grow and divide but tamoxifen prevents oestrogen from causing breast cancer cells to grow, helping to lower the risk of the disease returning. Most women have breast cancers that are stimulated to grow by oestrogen but not all.

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.

Professor Sir David Lane, Cancer Research UK's chief scientist said: "Cancer Research UK's early clinical trials of tamoxifen helped transform the way that women were treated for early breast cancer saving ten's of thousands of lives, and this work is yet another step forward.

"More women are surviving breast cancer than ever before thanks to improvements in diagnosis and treatment as well as important fundamental science discoveries like this."

He added: "Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women.

"Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments."