University of New Mexico Health Sciences Center
| By Cathleen Rineer-Garber, Communications and Publications Manager |
Collaborating scientists from the University of New Mexico and New Mexico State University have made a remarkable breakthrough in breast and women’s cancers. Publishing in two top tier medical research journals, Science and Nature Cell Biology, this team has discovered a novel receptor for the female hormone estrogen. This discovery will have a dramatic impact on our understanding of how women get breast and other female cancers and will lead us to better diagnostics and therapies for these diseases.
Eric Prossnitz, PhD, Professor of Cell Biology and Physiology at UNM, along with colleagues at the UNM Cancer Center and the Department of Chemistry and Biochemistry at New Mexico State University who are members of the UNM Cancer Center’s Women’s Cancers Research Program, discovered that a novel G-protein coupled receptor on cell surfaces known as GPR30 binds estrogen.
Discovery of a new estrogen receptor is important because estrogen is believed to stimulate the growth of some types of breast, uterine, and ovarian cancer. For years, estrogen has been a suspected carcinogen; last December, the hormone was added to the National Institute of Environmental Health Sciences list of known cancer-causing agents.
Estrogen receptors, like GPR30, contain a specific site to which only estrogens (or closely related molecules) can bind. When estrogen molecules circulate in the bloodstream, they affect only the cells that contain estrogen receptors. In some tissues, the main effect of estrogen is to cause cells to grow and divide – a process called cell proliferation. Although estrogen does not appear to directly cause cancer, it does stimulate proliferation of some cancer cells, such as in breast or endometrial cancer.
If a person already possesses a mutated gene that increases the risk of developing cancer, the cells will proliferate (along with normal breast cells) in response to estrogen stimulation. The increase in the total number of mutant cells may lead to the onset of cancer.Partnering with a team of chemists from NMSU led by Jeff Arteburn, PhD, the UNM School of Medicine Division of Biocomputing led by Tudor Oprea, PhD, and Chemical Diversity Labs, Inc., the team began to explore the function of GPR30. Within a year, they discovered that a compound designated G-1 selectively binds to and activates GPR30, preferring it to traditional estrogen receptors by more than one thousand fold. By taking advantage of this preference, Prossnitz believes that G-1 will become an important tool in further investigations of hormone signaling and the role of estrogen in the development of cancer.
“This finding presents multiple possibilities,” says Prossnitz. “For instance, the compound may be tagged to conventional chemotherapy treatments and then sent directly to cancer cells that contain high levels of GPR30. It may also be used as an imaging and therapeutic agent in conjunction with radioisotopes.” The potential for developing new drugs that target estrogen receptors is great, but this discovery may also have a significant effect on drugs currently being used to treat hormone-related diseases such as breast cancer. The most widely used therapy for receptor-positive breast tumors is tamoxifen, which blocks estrogen from binding to its receptors, and in doing so, prevents the tumor from growing. Millions of breast cancer patients worldwide have used tamoxifen, which dramatically reduces the risk of tumor recurrence.
Some patients, however, have little or no response to tamoxifen or similar drugs. Prossnitz and his colleagues found that GPR30 responds to tamoxifen differently than traditional estrogen receptors. Rather than blocking its action, tamoxifen activates GPR30. Further study of GPR30 — with the aid of compounds like G-1 — may help explain why some tumors appear to be unaffected by the drug. A research team led by Prossnitz has already begun exploring the possibilities for breast, endometrial and ovarian cancer treatment.
“We are very excited about these findings,” says Melanie Royce, MD, Associate Professor of Medicine and Director of Multidisciplinary Breast Cancer Program at the UNM Cancer Center. “Additional studies are planned to further clarify the role of GPR30 in several tumor types including breast cancer. We expect to find important links between GPR30 and cancers.”
Further research on GPR30 and the discovery of new cancer drugs and treatments has been facilitated with the opening of the New Mexico Molecular Libraries Screening Center (NMMLSC). Led by Larry Sklar, PhD, Associate Director of Basic Research at the UNM Cancer Center, the NMMLSC was established through a $9 million grant from the National Institutes of Health’s Roadmap Initiative. The center was one of only 10 new cancer drug screening centers funded throughout the U.S. under this program.
As part of this ten-member national collaborative research network, the NMMLSC will use high-throughput screening methods to identify small molecules that can be used for the development of new and more effective cancer therapies. “The advanced tools and technology available through the NMMLSC will enhance our ability to find new compounds with the potential of being developed into novel drugs,” says Sklar.
Ideally, says Prossnitz, the team’s research will result in a compound that will inhibit growth of GPR30-expressing cells, but that remains to be seen. For now, the team will continue its search for more promising compounds and work to fully understand the function of GPR30. In the process, they will provide hope to the more than 300,000 people who are newly diagnosed with hormone-related cancer each year.
The NMMLSC has already issued 9 patents, 6 licenses for new technologies, and has developed one new start up company: Sage Science.
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