Plant's Natural Product Helps Limit Growth of Breast Cancer
Madison, Wisconsin - In another major finding in University of Wisconsin breast-cancer research, a team of UW Carbone Cancer Center scientists has identified a naturally occurring compound that helps restore controlled growth in breast cancer cells.
The discovery, which may help put the brakes on the uncontrolled growth of cancer cells, should lead to more effective treatments for the disease.
Estrogen receptor alpha (ER-alpha), a protein that signals cells to grow in response to estrogen, is expressed in 70 percent of all breast cancers. Current endocrine therapies, such as tamoxifen or fulvestrant, work to inhibit or degrade it, but resistance to those drugs often occurs in recurrent breast cancer.
Although a second form of estrogen receptor, ER-beta, is also expressed in 70 percent of all breast cancers, including a subset of the “triple negative” breast cancers that do not express markers including ER-alpha, the protein level is often very low.
“ER-beta and ER-alpha have a yin and yang relationship in regulating cell growth: ER-alpha promotes and ER-beta inhibits cell growth,” said Dr. Wei Xu, professor of oncology at the Carbone Cancer Center. “However, unlike ER-alpha, ER-beta has not been a very good therapeutic target because its levels typically decrease as breast cancer progresses.”
ER-beta is rarely mutated at the DNA level, but its protein production is hampered in many breast cancers. Because it would be difficult to increase how much of it is made, Xu and her research team instead sought to identify a small molecule that could stabilize any ER-beta that is made, effectively increasing its protein levels in cancer cells.
The researchers treated breast cancer cell lines with many naturally occurring phytoestrogen compounds, a group of molecules with estrogen-like properties they reasoned might interact with estrogen receptors. They monitored changes in the two ER levels over time, hoping to find at least one compound that increased ER-beta levels but did not increase ER-alpha levels. They identified a compound called Diptoindonesin G (Dip G), isolated from the bark of some tropical plants, which fit both criteria - with an added bonus.
“We were very fortunate to find a compound that not only increased levels of ER-beta but also decreased ER-alpha,” Xu said. “No one has found a compound with this property yet.”
Xu hopes to develop Dip G as a new therapeutic compound for the treatment of broad subtypes of breast cancers. Due to its ability to decrease ER-alpha protein, Dip G may be used as the first line of therapy for breast cancers that express ER-alpha or as the second line of therapy to overcome endocrine therapy resistance.
The study also suggests that Dip G can enhance existing endocrine therapies to reduce the mortality associated with metastatic breast cancer. Importantly, by increasing ER-beta levels, Dip G may also enable ER-beta directed therapy in “triple negative” breast cancers toward which targeted therapy is not yet available.
Xu’s lab has been working on targeting estrogen receptors in breast cancer by identifying natural occurring molecules that function distinctly from the existing endocrine therapy agents. She said this work builds nicely, if not timely, off of work her lab published in 2008.
“We had previously identified other compounds that have an anti-proliferative effect, but only in cell lines where ER-beta levels were genetically engineered to be equal to or greater than ER-alpha levels,” Xu said. “These compounds would have little benefit clinically until ER-beta levels are elevated, which we can now do with the Dip G treatment.”
The study appeared in Chemistry & Biology and was supported by a Department of Defense ERA of HOPE Scholar award (W81XWYH-11-1-0237).
Date Published: 12/03/2015