Tamoxifen Resistance Scientists have identified a likely reason why 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. 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.” After several years of treatment, however, it begins to lose effectiveness. Researchers from Duke University Medical Center and Novalon Pharmaceutical Corp. reported in the July 30 issue of Science that instead of acting like either an estrogen or anti-estrogen, tamoxifen actually has its own distinct properties that drive the cell’s estrogen receptor in to 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, an additional and unique “pocket,” a place where other proteins inside the cell can bind to or dock themselves, is formed. These proteins have not yet been identified, but the researchers say that their action of binding to the new pocket on the receptor is what changes the cell’s response to tamoxifen. For reasons unknown, the cells begin to see tamoxifen as an estrogen instead of an anti-estrogen and the cancer once again proliferates. “We can attack the tamoxifen resistance problem from two fronts: a completely new drug that has all the benefits of tamoxifen but does not induce resistance, and a drug derived from a protein that blocks the estrogenic properties of tamoxifen,” says Donald McDonnell, a Duke pharmacologist and lead author of the study report. “Both are plausible next steps in the fight against estrogen-sensitive breast cancers.” Finding a drug that offers the best of both worlds seems to be the goal. Until then, tamoxifen will likely remain the “tried and true,” front-line defense against breast cancer.
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