Scientists unravel breast cancer drug resistance

• Cancer • • Breast Cancer • Nov 13, 08

British scientists have figured out why some women develop resistance to the most commonly used breast cancer drug, something that raises the risk their tumours will return, according to a study published on Wednesday.

The findings could lead to new tests to determine which women are not likely to benefit from tamoxifen and who should be given other drugs, said Jason Carroll of Cancer Research UK in Cambridge, who led the study published in the journal Nature.

“We can use this information to predict which patients will respond to tamoxifen and more importantly which ones won’t,” Carroll told reporters in a telephone briefing.

“More importantly it gives us an idea of what we should be making drugs against.”

Breast cancer is the leading cause of cancer deaths among women worldwide, according to the American Cancer Society. The group estimates about 465,000 women died of breast cancer globally in 2007, and 1.3 million new cases were diagnosed.

Declining death rates from breast cancer in developed countries have been attributed to early detection through mammography screening and to improved treatment.

Tamoxifen is given to most women for five years after they are diagnosed with breast cancer to prevent the disease from returning, but some women develop resistance, which means their tumour is more likely to recur.

The drug works by blocking oestrogen from causing wild cell growth in breast cancer by switching certain genes on, but how this exactly happened was unknown, the researchers said.

“Previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked,” Carroll said. “Now we understand how all the engine parts operate and we can try to think about ways to make repairs.”

Using microarrays - gene chips - to scan millions of DNA sequences, the researchers investigated what was happening in genes known to play a key role in breast cancer.

For tamoxifen to work properly it has to block a gene called HER2, which it does by using a control switch hidden within the gene itself, the researchers said.

But for this to happen a protein called Pax2 must keep the switch in the off position - something that appears to fail for women who develop resistance, the researchers said.

The findings mean some women should potentially be directly given other drugs currently on the market such as Genentech’s Herceptin or aromatase inhibitors like AstraZeneca’s Arimidex, Carroll said.

“It turns out we knew where the genes were but finding out where the switch was located was the difficult part,” Carroll said. “Pax2 is the handle that keeps the switch off.”

By Michael Kahn
LONDON (Reuters)