Although tamoxifen first came into use to treat breast cancer more than 30 years ago, understanding of its actions has increased with the findings that it causes cancer cells to re-express the tumor suppressor gene called maspin, according to an article in the January 15th issue of Clinical Cancer Research. The discovery could lead to better targeting of the therapy and possibly the development of new anti-cancer drugs.

The maspin protein, which is abundant in normal breast cells, has been shown to inhibit tumor invasion and metastasis. However, in breast cancer, maspin gene expression is diminished or lost. Previous studies had shown that reintroduction of maspin into breast cancer cells that have lost gene expression causes the tumors to be less invasive.

The current study showed that treatment with tamoxifen turned on maspin expression in cells of a breast-cancer line that had lost it. Moreover, the researchers found similar results in tissue samples from breast cancer patients who had been treated with successfully 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, PhD, 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 in treating and, in some cases, preventing breast cancer, the drug has two significant problems. Long-term use of tamoxifen 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 authors also suggested that current tamoxifen treatment regimens should be reevaluated to monitor how tamoxifen controls maspin expression and to 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, PhD, the senior investigator. "Following a tumor suppressor gene such as maspin offers a unique opportunity to track the efficacy of chemotherapy both during and after therapy."