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Scientists Unravel Mystery of Tamoxifen Resistance
Date:11/12/2008

Some breast tumors produce a protein that defeats the drug

WEDNESDAY, Nov. 12 (HealthDay News) -- As many as 35 percent of women who take tamoxifen to prevent the return of breast cancer do not respond to the drug -- and now scientists think they know why.

A battle between proteins to turn a breast cancer gene off or on determines if tamoxifen works or not, the scientists report. The finding could be used to spot those women who won't respond to the drug, and it may even lead to new therapies.

"Given the fact that tamoxifen is such a commonly prescribed drug for the treatment of breast cancer, understanding how it works and what happens when it fails is critical to making better drugs," Jason Carroll, from the Cancer Research UK Cambridge Research Institute, said during a Tuesday teleconference on the research.

His team published its report in the Nov. 12 online edition of Nature.

Tamoxifen resistance is a significant problem, affecting 25 percent to 35 percent of breast cancer patients, the authors said.

Now, the puzzle of resistance to the drug may be solved.

"For tamoxifen to work, it has to be able to switch off a very powerful cancer gene," Carroll said. Tamoxifen stops tumor growth by binding to the estrogen receptor and blocking the HER-2 gene, which otherwise causes cancer cells to divide. "If this switch fails, cancer cells become tamoxifen-resistant and tamoxifen is no longer effective," Carroll explained.

In the study, Carroll's team found how this gene can be switched on and off.

The switch for the HER2 gene is hidden within the gene, Carroll said. That switch is a signaling molecule called PAX2. "PAX2 is the handle that keeps HER2 switched off," he said.

If PAX2 isn't there -- or is forced out by another protein called AIB-1 -- the switch fails, Carroll said. "It's a tug of war," he said. "It's a competition between PAX2 and AIB-1. The
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Scientists Unravel Mystery of Tamoxifen Resistance
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