Affymetrix Inc., (Nasdaq:AFFX) announced today that scientists at Cancer Research UK have used Affymetrix technology to discover the molecular basis for tamoxifen response in breast cancer cells – and the reason why some women can develop resistance to the treatment. Their findings are published in Nature1.

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. 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 estrogen from causing unchecked cell growth in breast cancer by switching certain genes on, but the mechanism by which this occurred was unknown.

“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,” said Dr Jason Carroll, lead author on the study. “Now we understand how all the engine parts operate and we can start to think about ways to make repairs.”

“Using the GeneChip® Human Tiling 2.0R Array Set, we have discovered that for tamoxifen to work it has to block the gene ErbB2. 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 estrogen can cause breast cancer cells to grow and divide and tamoxifen prevents estrogen 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 estrogen, but not all.

Breast cancer is the most common cancer among American women. More than 250,000 new cases will be diagnosed this year, and more than 40,000 women will die from the disease in 2008, according to the American Cancer Society. There are currently about 2.5 million survivors in the country2.

“Cancer Research UK’s early clinical trials of tamoxifen helped transform the way that women were treated for early breast cancer, saving tens of thousands of lives, and this work is yet another step forward,” said professor Sir David Lane, Cancer Research UK’s chief scientist. “More women are surviving breast cancer than ever before thanks to improvements in diagnosis and treatment as well as fundamental science discoveries like this.”

“Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women,” added Lane. “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.”

“GeneChip® Tiling Arrays have enabled high-resolution, genome-wide mapping of estrogen receptor (ER) binding sites,” said Kevin King, president of Affymetrix. “This study demonstrates the power of using this approach to resolve a single important ER binding site that plays a key role in determining the mechanisms underlying tamoxifen resistance in breast cancer. It has the potential to significantly improve prescription decisions related to this leading drug treatment.”

1Hurtado A., et al. ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response, Nature. November 12 2008.

2From the American Cancer Society webpage: What Are the Key Statistics for Breast Cancer? https://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_breast_cancer_5.asp?sitearea=