Tamoxifen in action

Views of tamoxifen and synthetic estrogen in action provide clues for designing better drugs

December 23, 1998

Researchers from the University of Chicago Medical Center and the Howard Hughes Medical Institute at the University of California at San Francisco have discovered the molecular mechanism by which tamoxifen blocks the effects of estrogen, a process that has been shown to prevent breast cancer in some women at high risk.

The results, published in the December 23, 1998 issue of Cell, provide valuable clues about ways to design new, more effective disease-preventing medications with fewer side effects.

"The goal is to figure out how to make drugs that retain the benefits of estrogen for brain, bone and heart and also have the benefits of estrogen blockers for the breast and uterus," said Geoffrey Greene, PhD, professor in the Ben May Institute of Cancer Research at the University of Chicago and a senior author of the study. "Now we have precise three-dimensional shapes of the complex that forms between several of these molecules and the estrogen receptor."

"These structural studies clarify how estrogens turn on genes and show precisely how tamoxifen blocks this process," said first-author Andrew Shiau, a graduate student in biochemistry and biophysics at the University of California, San Francisco (UCSF). "This sets the stage for intentional design of drugs with precise and selective action."

Estrogen has many health benefits. It delays the buildup of artery-clogging plaque, prevents bone loss leading to osteoporosis, and may even postpone the onset of Alzheimer's disease. These benefits disappear at menopause when women stop making significant amounts of estrogen. Although taking replacement estrogen can restore these benefits and prevent the hot flashes of menopause, continued exposure to this hormone increases a woman's risk of breast or uterine cancer.

Designer estrogens, also known as selective estrogen receptor modulators (SERMs), are a class of drugs that function like estrogen in some tissues but block estrogen's actions in others. The best known SERM is tamoxifen, which recently received FDA approval for breast cancer prevention.

But tamoxifen is flawed. It may block the potentially harmful action of estrogen in the breast, preserve estrogen's beneficial effects for bone maintenance and some of its cardiovascular effects, but unfortunately, it also retains estrogen's tendency to promote uterine cancer. Another SERM, raloxifene, appears to have similar benefits with less risk of uterine cancer. The two will be compared head-to-head in a large clinical trial beginning next year.

"Both are useful drugs but neither is ideal," said Greene. "As we learn more about how they interact with the estrogen receptor, we should be able to enhance their benefits and reduce their drawbacks."

Greene's Chicago predecessor Elwood Jensen determined in the 1950s that estrogen works by binding to a specific receptor, found only in certain types of tissues. Once contacted by estrogen, the receptor relays the message to turn on specific genes.

More recently, researchers have discovered that estrogen action is not a simple on-off signal. When the ligand occupies its binding site on the receptor, it triggers a change in the three-dimensional shape of the receptor that creates a docking site for either co-activators or co-repressers--proteins which when bound enhance or suppress the activity of the receptor. The shape change that's induced varies according to the nature of the compound, whether it's a full estrogen, a full anti-estrogen, or a mixed estrogen/anti-estrogen such as tamoxifen.

Thus, the signal mediated by the estrogen receptor inside a target cell can result in either an increase or decrease in the growth response to a given compound, which appears to influence how tissues respond differently to SERMs.

In the Cell paper, the researchers describe how tamoxifen alters the normal shape of the receptor in a way that covers up a co-activator binding site that is ordinarily exposed by estrogen or by synthetic estrogens such as DES. Tamoxifen causes one region of the receptor to rotate out of place, not only preventing it from functionin--but packing it into a groove where a co-activator protein is thought to bind.

A related paper from the University of York, published a year ago, found a similar difference between the effects of estradiol--a form of estrogen--and raloxifene. But the UCSF/University of Chicago paper in Cell is the first to connect these structural changes with alterations in coactivator binding to the estrogen receptor. The UCSF/Chicago investigators have also noted some slight differences between the three-dimensional shapes of the receptor bound to tamoxifen and to raloxifene. This may lead to a better understanding of the different biology of these two compounds in tissues like the uterus.

"Our work doesn't provide the blueprint for the perfect replacement estrogen," said Greene, "but this collection of receptor structures--first estradiol and raloxifene, and now DES and tamoxifen--offers us the best clues to date about how to begin to design new drugs."

The other senior author of the paper is David Agard, professor of biochemistry and biophysics and Howard Hughes Medical Investigator at UCSF. Other authors are: Peter Kushner, also of UCSF; and Danielle Barstad, Paula Loria, and Lin Chang from the University of Chicago. Researchers in Greene's laboratory initiated the study and crystallized the proteins. The structures and their molecular-level function were determined using X-ray crystallography in Agard's laboratory. Funding for the study was provided by the United States Army, the National Cancer Institute, the American Cancer Society, and the National Institutes of Health.

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