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GUMC researchers say flower power may reduce resistance to breast cancer drug tamoxifen
Date:2/16/2010

chers set out to study if, as previous research had suggested, tamoxifen resistance is regulated by the protein complex NF- κB (nuclear factor kappa B), which is often found to be over-expressed in ER+ breast cancer. NF- κB is known to help cells survive when damaged.

The researchers had earlier discovered that NF- κB is over-expressed in cells that are resistant to tamoxifen, and they had found that resistance to another tamoxifen-like drug, fulvestrant, was controlled by a protein (Bcl2) that is, itself, regulated by NF- κB.

"Our scientific quest was to see if blocking NF- κB affects tamoxifen resistance, and if it does, why?" says Clarke.

They conducted a variety of tests using parthenolide, which has been shown to act on NF- κB. They found that in resistant breast cancer cells, the chemical blocked the activity of NF- κB, making the cells sensitive once again to tamoxifen. They then silenced NF- B in tamoxifen resistant cells, and found that this had the same effect as using parthenolide.

They further found that increased activation of NF- κB can alter sensitivity of tamoxifen by modulating the protein CASP8, which is involved in programmed cell death. That then affects Bcl2, which also helps push a damaged cell to die.

"When you give tamoxifen to a breast cancer cell, that is essentially a pro-death signal, because you are blocking the cell's access to estrogen, and the cell recognizes this is a mortal blow," Clarke says. "Such a damaged cell uses CASP8 and Bcl2 to trigger the cell machinery needed for dying.

"But the cell has ways to counteract the pro-death signal, and one important one is to activate NF- κB, which can control expression of genes necessary for survival," he says. "Now the cell thinks it should be living, not dying."

Because NF- κB controls CASP8 and Bcl2, it can turn those proteins essentially off, Clarke says. "The pro-survival signals override th
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Contact: Karen Mallet
km463@georgetown.edu
215-514-9751
Georgetown University Medical Center
Source:Eurekalert

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