The scientists used two estrogen-sensitive human breast cancer cells lines, one that was sensitive to tamoxifen and produced low levels of TGF-beta and a daughter cell line that was resistant to tamoxifen and overproduced TGF-beta. The cells were used to create tumors in mice, which were then treated with tamoxifen.
Tumors with low TGF-beta levels responded to tamoxifen, while the tumors formed by the cells that overproduced TGF-beta did not. However, when antibodies to block TGF-beta were added to tamoxifen, these resistant tumors became sensitive to the drug. "This suggested to us that TGF-beta was mediating the resistance to the anti-estrogen," Arteaga said.
When the cell lines were studied in culture rather than in the animal, however, adding TGF-beta antibodies did not restore tamoxifen sensitivity. This strongly suggested that something in the mouse -- but absent in the cell cultures -- was involved in the development of tamoxifen resistance.
The researchers suspected that the mechanism was the host's "natural killer" (NK) immune activity for two reasons. First, tamoxifen is known to increase NK activity. Second, TGF-beta is a powerful suppressor of NK function. So if tamoxifen needs to increase NK activity to be effective, and if TGF-beta decreases that activity, it would make sense that increased TGF-beta levels would result in a reduced anti-tumor effect by tamoxifen.
To test their hypothesis, the researchers repeated the experiment in "beige
mice," which lack natural killer activity. They found that the combination of
tamoxifen and TGF-beta antibodies did not have an anti-tumor effect in the beige
mice bearing tamoxifen-resistant tumors. In addition, they discovered tha
Contact: Cynthia Manley
Vanderbilt University Medical Center