A team of researchers at the University of New Mexico Cancer Center have discovered a new compound that regulates cell responses to estrogen, which could have exciting implications in the fight against breast, uterine, endometrial and ovarian cancers. The report, published today in the online version of the journal Nature Chemical Biology, builds on previous findings by the UNM Cancer Center team, and furthers our understanding about estrogen’s role in cancer development.
As estrogen circulates through the bloodstream, it only binds to those cells that have estrogen-specific receptors, much like a key fits into a specific lock. Once the hormone has bound to the cell receptor, it starts a chain of reactions, activating various pathways that allow the cell to perform important tasks in the reproductive, nervous, immune and vascular systems, such as reproduction and moderating blood pressure and emotions. Estrogen is also known to stimulate cell growth and is believed to play a role in cancer’s uncontrolled cell growth. In December 2006, the hormone was added to the National Institute of Environmental Health Sciences list of known cancer-causing agents, so a better understanding of estrogen-regulated cell function has long been a goal of researchers.
In 2005, the UNM Cancer Center, working with New Mexico State University researchers, published findings of a newly identified estrogen receptor, GPR30. The discovery continues to have a dramatic impact on the understanding of how women develop estrogen-related cancers, as this receptor was unrelated to already-known receptors. UNM Cancer Center scientists worked quickly to further study the receptor’s functions. Shortly thereafter, they identified a compound that bound only to GPR30 receptors and mimicked estrogen’s ability to stimulate cell proliferation through this receptor. That compound, known as G-1, has been studied in institutions around the world, generating more than 20 subsequent scientific papers.
Now, UNM Cancer Center researchers have discovered a new compound that also selectively binds only to GPR30, but has the opposite effect of G-1. The compound, known as G15, inhibits cell proliferation by preventing estrogen from binding to certain cells, specifically blocking access to GPR30 without affecting other estrogen receptors. Scientists are excited to find such a molecule, as it could lead to new drug therapies and treatments.
“GPR30 is a newly identified receptor for estrogen and its actions in the body are still not fully understood,” said Eric Prossnitz, Ph.D., Director of the Women’s Cancers Research Program at the UNM Cancer Center and principal investigator of the study. “The development of new compounds that can specifically activate or inhibit this receptor provides opportunities to discover how this receptor contributes to the vast array of physiological effects mediated by estrogen. In particular, targeting the activity of GPR30 in chemotherapy-resistant or hormone-resistant cancers may provide a new approach to treat many cancers.” In a separate study, the team found that high expression of GPR30 predicted poor survival in endometrial cancer. By providing a compound that “turns off” GPR30, researchers could essentially reduce GPR30 function, which could decrease mortality rates associated with certain cancers.
The findings could have potential for other diseases as well. For example, estrogen is known to affect the immune system and reduce the severity of multiple sclerosis outbreaks, but is not a good treatment because of the increased risk of breast and uterine cancers. “But if you knew molecularly how to replicate some of estrogen’s beneficial actions without enhancing the negative aspects, you might have a good therapeutic agent,” Prossnitz said.
Although the study was led by researchers at the UNM Cancer Center, the team collaborated with scientists at New Mexico State University and across the country. “This publication marks a dramatic accomplishment of a multidisciplinary team of teams. Starting with Dr. Prossnitz’s biological team, it includes a discovery team led by Dr. Tudor Oprea and myself, a synthesis team led by Dr. Jeffrey Arterburn at New Mexico State University, and physiology teams lead by Dr. Helen Hathaway at UNM and Dr. Nae Dun at Temple University in Philadelphia,” said Larry Sklar, Ph.D., Director of the UNM Center for Molecular Discovery. “It is a tribute to the state of New Mexico that such expertise has assembled here.”
The UNM Cancer Center is the Official Cancer Center of the State of New Mexico, and one of only 63 National Cancer Institute designated cancer centers in the nation. It is home to 85 board-certified oncology physicians representing every cancer specialty and more than 120 research scientists hailing from such prestigious institutions as M.D. Anderson, Johns Hopkins and the Mayo Clinic. Last year, the UNM Cancer Center served more than 7,600 new patients in 84,000 patient visits.