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Duke/Novalon researchers identify potential mechanism behind tamoxifen resistance in breast cancers

DURHAM, N.C. -- Scientists have identified a likely reason why the breast cancer drug tamoxifen stops working in women who use it for more than five years. They say their discovery could lead to new drugs that either work better than tamoxifen or prevent a woman's resistance to the drug.

The researchers, from Duke University Medical Center and Novalon Pharmaceutical Corp., reported in the July 30 issue of Science that tamoxifen initiates a cascade of changes inside the breast cell that are far different from the effects of estrogen or other compounds that rouse the estrogen receptor into action.

Tamoxifen's desired action is to block the effects of estrogen, a hormone involved in the growth of half of all breast cancers. It works by binding to the estrogen receptor and blocking estrogen from docking to it. Hence, tamoxifen has been called an "anti-estrogen." Later, however, tamoxifen begins to lose its effectiveness, and researchers have long wondered why.

Now, they have learned that instead of acting like either an estrogen or an anti-estrogen, tamoxifen has its own distinct properties that drive the cell's estrogen receptor into a different shape than estrogen or other estrogen "mimics" would. The shape the receptor takes determines how the cell will behave and what activity it will generate.

In the case of tamoxifen, the researchers found that it causes the estrogen receptor in breast cells to form an additional and unique "pocket" or surface -- a place where other proteins inside the cell can bind to or dock themselves. While these proteins have yet to be identified, the researchers say their action of binding to this new pocket on the receptor is what changes the cell's response to tamoxifen. For reasons unknown, the cells then begin to see tamoxifen as an estrogen instead of an anti-estrogen, and hence the cancer once again proliferates.

"The implications of our discovering this new pocket fo
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Contact: Rebecca A. Levine
Levin005@mc.duke.edu
919-684-4148
Duke University Medical Center
30-Jul-1999


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