The Oncologist, Vol. 7, No. 2, 163-164,
April 2002
© 2002 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: Tamoxifen and the Estrogen Receptor
David S. Goodsell
Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell
Our bodies grow in two major spurts during our lives. You probably don’t remember the first, which occurred in your first months of life as you grew from a single cell to a fully formed baby. On the other hand, you probably have far too many memories of your second frenzy of growth, during puberty. During puberty, sex hormones direct selected tissues throughout the body to make changes, making us ready for adulthood. If all goes well, these signals then gracefully shut down, and we keep our adult bodies for the rest of our lives. If signals get crossed, however, hormones can ask for unnatural growth at improper times, leading to cancer.
Many forms of breast cancer are examples of faulty messages sent by sex hormones. The hormone estrogen is largely responsible for coordinating the changes that occur in women during puberty, including the growth of breasts. Estrogen (Fig. 1
) is a small, carbon-rich steroid molecule made in the ovaries. It is delivered to cells throughout the body by serum proteins in the bloodstream. Within seconds, it slips through cell membranes and ends up in the nucleus. It binds to a complex receptor protein, the estrogen receptor (Fig. 2), which then controls the synthesis of key proteins involved in growth.
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Figure 1. Estradiol and tamoxifen. Estradiol, shown at the top, is a small carbon-rich steroid. Tamoxifen, shown at bottom, mimics the shape and chemical composition of estradiol. Tamoxifen, however, has an extra chain attached in the middle that is important for its antagonistic action.
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Figure 2. The estrogen receptor. The estrogen receptor is a protein with several functional parts: a DNA-binding domain, two activation domains, and an estrogen-binding domain. The estrogen-binding domain (blue) and the associated activation domain AF-2 (green) are shown here. Estradiol binds deep within a pocket in the receptor and is covered by a loop of protein chain, as shown in the upper illustration (estradiol is covered by the loop in green—on the left-hand subunit, the loop is transparent to show estradiol underneath, in pink). This loop forms part of the activation signal that will stimulate growth in the cell. However, when tamoxifen (in pink in the lower illustration) binds, the extra tail of the drug is too bulky and the receptor loop is not able to adopt its active conformation. Coordinates were taken from entries 1qku and 3ert from the Protein Data Bank (http://www.pdb.org).
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In many breast cancers, the presence of estrogen provides "permission" for the cancer cells to grow. Mutations in one or more oncogenes directly cause the uncontrolled growth, and estrogen then promotes the growth of the cancer. The drug tamoxifen rescinds this permission by blocking the reception of the estrogen message. Tamoxifen binds to the estrogen receptor but does not activate it fully, halting estrogen-induced growth.
Of course, estrogen has many effects throughout the body. It is dangerous to block its action indiscriminately. For instance, estrogen is also important in bone growth, and blocking of estrogen action may lead to osteoporosis. Tamoxifen, however, is serendipitously specific. It is chemically very similar to estrogen, and binds in the same site on the estrogen receptor as the normal hormone. Tamoxifen is not a typical inhibitor, blocking action completely. It is found to have a range of effects, sometimes blocking the action of the receptor, but other times actually activating it. This difference in action may be due to the many other proteins that interact with the receptor and the DNA. In any case, tamoxifen shows a remarkably attractive combination of clinical effects. The drug blocks growth in cancer cells, providing protection for many patients. However, tamoxifen appears to act like estrogen in bone cells, actually providing the proper signals for bone maintenance.
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FURTHER READING
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 Top
 Further Reading
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Macregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998:50;151–196.[Abstract/Free Full Text]
Shiau AK, Barstad D, Loria PM et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998:95;927–937.[CrossRef][Medline]
