MADISON—About six in 10 breast cancer cases are caused when estrogen triggers cell receptors to promote abnormal cell growth leading to tumors. But if two particular receptors come together in what a University of Wisconsin-Madison researcher calls a "yin yang" relationship, one might knock down the activity of the other and breast cancer growth could be halted.

For the first time, researchers at the School of Medicine and Public Health used a test that shows how molecules interact to "see" how both receptors-estrogen receptor (ER) alpha and ER beta--co-exist inside cells.

ER alpha is known to promote the abnormal cell growth that leads to the formation of tumors while ER beta inhibits tumor cell growth and promotes the death of these cells. The SMPH researchers found that ER alpha is the dominant partner that brings the two receptors together in a more balanced way.

The research, conducted by graduate student Emily Powell and Wei Xu, SMPH assistant professor of oncology at the McArdle Laboratory for Cancer Research (pictured above), appears in the Proceedings of the National Academy of Sciences Online this week (Nov. 10-14, 2008).

Xu believes that the new test developed in her lab can be used to tell if a particular compound promotes the favorable "yin yang" relationship.

"We want to identify agents that make ER beta pair with ER alpha, in a structure called a heterodimer, potentially allowing the beta to dampen the alpha activity," says Xu, lead author of the study. "We think this might be a valid approach for developing a new line of therapy for breast cancer treatment and prevention."

The researchers used the Bioluminescence Resonance Energy Transfer (BRET) test to evaluate two naturally occurring compounds thought to have potential as breast cancer and menopause treatments: genistein, a component of soy, and the Chinese herb called liquiritigenin.

'We found that genistein induces pairing of ER alpha with itself equally as well as pairing with ER beta," says Xu. "This may explain why genistein has shown conflicting results in clinical trials."

On the other hand, liquiritigenin, which has been tested in a clinical trial for treating menopause symptoms, favors ER beta-ER beta pairing and ER alpha/ER beta heterodimers while not promoting the formation of the cancer-stimulating ER alpha-ER alpha pairs.

"This study changes the way we view how natural compounds might work in the human body," says Xu, a member of the UW Paul P. Carbone Comprehensive Cancer Center.

Breast cancer is the second leading cause of cancer death among U.S. women. In 2008, 3,400 Wisconsin women will develop the disease. Current treatments, such as tamoxifen and aromatase inhibitors, prevent estrogen from binding to estrogen receptors. But many patients develop resistance to the drugs, and tamoxifen can lead to endometrial cancer.

Xu and her team are hoping to use the BRET test to screen a natural-compound library for estrogen-like substances that have an affinity for heterodimer formation.

"We hope to identify dietary constituents that can be eaten to lower the risk of breast cancer," she says. "Diet is one of the most critical non-genetic ways to prevent breast cancer."