Vanderbilt Cancer Center Discovery May Help Overcome Resistance To Anti-Breast Cancer Drug

Writing in the Jan. 6 issue of the Journal of the National Cancer Institute, the researchers report that overproduction of a certain growth factor, called TGF-beta, contributes to tamoxifen resistance. They also demonstrate that the immune system's "natural killer" activity is important for tamoxifen's anti-cancer effects.

Ultimately, both findings might be exploited to keep tumors dormant for longer periods using tamoxifen.

"At some point in the natural history of breast cancer, tumors become resistant to the anti-estrogen tamoxifen," said principal investigator Dr. Carlos L. Arteaga, professor of Medicine and associate professor of Cell Biology.

"The practical implication of this research is that, if we can sort out the mediators of this effect, perhaps we can design strategies to interfere with those mechanisms and markedly prolong the period of tamoxifen response or even reverse tamoxifen resistance."

Tamoxifen, a relatively well-tolerated therapy, has been a part of the arsenal against advanced breast cancer for more than two decades. More recently, it has been used as an additional therapy following surgery or other primary treatment for early stage breast cancer. Tamoxifen is also being studied as a "chemopreventive" to delay the onset of breast cancer in women at high risk of developing the disease.

The drug is called an anti-estrogen because it blocks the effects of the female hormone estrogen. Some breast cancer cells are sensitive to estrogen, which binds to estrogen receptors in these cells and stimulates them to proliferate and invade.

In patients with metastatic breast cancer, tumors typically become resistant to tamoxifen in about 12-18 months, Arteaga said.

Earlier work has suggested that some tamoxifen-resistant breast cancers produce abnormally high levels of transforming growth factor beta (TGF-beta). So Arteaga and his colleagues decided to test whether interfering with the production of TGF-beta would alter this resistance.

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 that in tamoxifen-sensitive tumors that produced low levels of TGF-beta, the effect of tamoxifen was statistically greater in the mice with NK activity than in those that lacked it.

"There are many potential ways, some in development, to inhibit TGF-beta, so I'm hopeful we can test combinations of these inhibitors with tamoxifen to see if we can enhance the effects of tamoxifen in women whose breast cancers overproduce TGF-beta," Arteaga said.

This research also has implications for patients whose NK activity is suppressed, Arteaga said. "It is not uncommon to see NK activity suppressed in patients with cancer, so we believe that, in some cases, NK function may be down-regulated by something that the tumor produces," he said.

"There are ways to boost NK activity, so perhaps we can use those to increase the response to tamoxifen."

The work was supported by the National Cancer Institute and the Susan G. Komen Breast Cancer Foundation.

More information about the Vanderbilt Cancer Center, which is designated as a leader in cancer care and research by the National Cancer Institute, can be found at the Vanderbilt Cancer Center website at http://www.mc.vanderbilt.edu/vumc/centers/cancer.