Feb. 3, 2004 IOWA CITY, Iowa -- First used to treat breast cancer more than 30 years ago, tamoxifen now is one of the most widely used breast cancer therapies. University of Iowa researchers have discovered a new mode of action for tamoxifen, which could lead to better targeting of the therapy and possibly the development of new anti-cancer drugs.
In breast tissue, tamoxifen acts as an anti-estrogen, meaning that it blocks the action of the hormone estrogen. Normal breast cells grow in response to estrogen in a controlled fashion. However, in breast cancer, this cell growth is out of control. Treatment with the anti-estrogen tamoxifen inhibits the uncontrolled cell growth and keeps cancer in check.
In a new study, which appears in the Jan. 15 issue of Clinical Cancer Research, researchers based at the Holden Comprehensive Cancer Center at the UI have identified another way that tamoxifen can prevent cancerous growth. The study indicates that tamoxifen treatment causes the re-expression of a tumor suppressor gene known as maspin.
Maspin protein has been shown to inhibit tumor invasion and metastasis, and in normal breast cells, maspin protein is abundant. However, in breast cancer, maspin gene expression is diminished or lost and tumors can form and spread unchecked. Previous studies have shown that reintroducing maspin into breast cancer cells, which have lost the gene expression, causes cancers to be less invasive.
The UI study showed that treatment with tamoxifen turned maspin expression back on in breast cancer cells that had lost the gene expression. The study suggests that one of tamoxifen's beneficial effects is due to its ability to turn maspin expression back on. Moreover, the researchers also found similar results in tissue samples from breast cancer patients who had been treated with tamoxifen.
"Looking at the tumor samples we found up-regulation of maspin in these samples too. That was further confirmation of what we saw in breast cancer cell lines," said Zhila Khalkhali-Ellis, Ph.D., UI associate research scientist and lead author of the study. "The importance of the study is that it demonstrates the ability of tamoxifen to up-regulate a tumor suppressor gene that has important consequences in inhibiting breast cancer invasion and metastasis. This has not been shown before. I think we can really use that information to improve treatment protocols."
Although tamoxifen has been proven clinically effective at treating and, in some cases, preventing breast cancer, this drug has two significant problems. Long-term use of tamoxifen, like many other cancer drugs, can lead to drug resistance and tamoxifen often causes unpleasant side effects. The finding that tamoxifen can up-regulate maspin expression may lead to the development of related drugs that can better target the maspin gene without producing side effects. The UI researchers also suggest that in light of this finding current tamoxifen treatment regimens should be reevaluated to monitor exactly how tamoxifen controls maspin expression and determine if different treatment protocols could maintain maspin expression while limiting drug resistance.
"In the best case scenario, longer exposure to tamoxifen results in a stronger re-expression of maspin for longer periods of time," said Mary Hendrix, Ph.D., the senior investigator on the study. "Following a tumor suppressor gene, such as maspin, offers an unique opportunity to track the efficacy of chemotherapy both during and after therapy."
In addition to Khalkhali-Ellis and Hendrix, the UI team also included Mohammad Vasef, M.D., associate professor (clinical) of pathology, who provided the breast tissue samples. Other researchers from Hendrix' laboratory involved in the study were Abby Christian, Dawn Kirschmann, Elijah Edwards, Maryam Rezaei-Thompson, Lynn Gruman, Richard Seftor and Laura Norwood.
The study was funded in part by the National Cancer Institute and the Marilyn Rozeboom Endowment.
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