Researchers Visualize Second Bonding Site for Popular Breast Cancer Drug

CINCINNATI—Researchers at the University of Cincinnati (UC) and Lilly Research Laboratories have confirmed the existence of a second binding site on one version of the estrogen receptor for the popular breast cancer drug tamoxifen.

This finding, they say, could lead to the design of new breast cancer drugs or prove important for breast cancer patients who encounter resistance to tamoxifen therapy.

Their results are reported in the June 12, 2006, online early edition of Proceedings of the National Academy of Sciences (PNAS). 

Tamoxifen, introduced more than 30 years ago for the treatment of breast cancer, is a drug that—at high concentrations—antagonizes estrogen action and prevents breast cancer cell growth. High concentration doses of tamoxifen have proven effective as a therapy for many breast cancer patients.

At low concentrations, however, tamoxifen has been shown to promote the growth of breast cancer cells.

UC professor and nuclear receptor expert Elwood Jensen, PhD, originally found this “dual action” of tamoxifen to be quite “curious pharmacology,” and his continued research indicated that there might be two binding sites for tamoxifen on the estrogen receptor.

In their new PNAS study, scientists led by Jensen and Tom Burris, PhD, of Lilly Research Laboratories, used X-ray crystallography to determine the structure of one of the versions (isoforms) of the estrogen receptor in the presence of tamoxifen. They were then able to pinpoint the two binding sites, clearly showing that tamoxifen does in fact connect to the estrogen receptor in two places. Estrogen, on the other hand, has only been shown to bind at one site.

Demonstrating the existence of two binding sites for tamoxifen could have implications for breast cancer drug development, the researchers said.

“In the search for more effective estrogen antagonists, the affinity for the second site should be an important factor,” they write.

Coauthor Sohaib Khan, PhD, UC professor of cell biology, is now working with his lab to further study the second tamoxifen binding site. His team will work to create “mutants” of the estrogen receptor to determine what happens to breast cancer cells when this newly found second site is abolished.

“Learning more about the two tamoxifen–binding sites—will really give us new clues for novel drug design and drug resistance,” said Khan.

More than 214,000 women will be diagnosed with breast cancer in 2006, according to the American Cancer Society, and 19 percent will die from it.

The study was funded by the National Institutes of Health.

Coauthors include Khan, University of Cincinnati, and Stephen Briggs, Nikolay Chirgadze, and Yong Wang, all of Lilly Research Laboratories.