CHAMPAIGN, Ill. -- Breast-cancer researchers at the University of Illinois
have identified four amino acids viewed as leading actors in the binding
of estrogen and anti-estrogen hormones to receptor proteins in the female
The findings could prove to be crucial in efforts to understand how the receptors respond to drug therapies and how they become resistant to tamoxifen, which, for 20 years, has been the anti-estrogen agent most commonly used against breast cancer in the United States, said lead researcher Benita Katzenellenbogen, a professor of molecular and integrative physiology.
The research was published in the Aug. 16 issue of The Journal of Biological Chemistry. The authors were Katzenellenbogen, who on Oct. 18 will receive the 1996 Komen Scientific Distinction Award from the Susan G. Komen Breast Cancer Foundation in Dallas; her husband, John Katzenellenbogen, professor of chemistry; Kirk Ekena, postdoctoral researcher; and Karen E. Weis, research associate.
The estrogen receptor is a protein containing about 600 amino acids. It takes in estrogen, providing the transcription signal (the message system) for biological activity important in bone maintenance, especially for postmenopausal women, and for cardiovascular protection. But estrogen also increases the risk of breast cancer in some women.
"We've identified portions of the hormone-binding domain of this protein that appear to be critical sites for binding with the hormone," Benita Katzenellenbogen said. "We've shown that if one alters one of these four amino acids then one eliminates the ability of estrogen to bind, and as a consequence one also eliminates the ability of these receptors to act as transcriptional regulators."
The research, funded by the National Institutes of Health, was conducted using a molecular biological technique called alanine-scanning mutagenesis, in which a different form of amino acid is substituted one at a time into specific positions along the receptor protein.
Anti-estrogens bind to the same receptor as estrogens. In fighting breast cancer, tamoxifen blocks the binding of estrogen, enabling the drug to work against the growth of cancer cells while still having beneficial effects on the heart and bones. But tamoxifen also has weak estrogen-like activity that has been linked to cancer of the uterus. It also loses its effectiveness as cancer cells become resistant to it.
Benita Katzenellenbogen is now focusing on how the receptors interpret the difference between estrogen and anti-estrogen and, in turn, activate appropriate genes or growth factors along the biological pathway in the body. Her lab also has developed models of tamoxifen-resistant human cells in an attempt to understand how resistance develops.
"Understanding these pathways should provide insight that should help in drug development for therapies that are more tissue selective," she said. "These studies are of enormous importance for the effective, long-term treatment of breast cancer."