In the new study, to be published in the February 2015 print edition of the journal Molecular Pharmacology, the scientists showed that the compound, known as SR1848, reduces the activity and expression of the cancer-related protein called “liver receptor homolog-1” or LRH-1.
“Our study shows that SR1848 removes LRH1 from DNA, shutting down expression of LRH-1 target genes, and halts cell proliferation,” said Patrick Griffin, chair of the TSRI Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida. “It’s a compound that appears to be a promising chemical scaffold for fighting tumors that are non-responsive to standard therapies.”
LRH1 plays a crucial role in breast cancer through its regulation of genes involved in hormone synthesis and cholesterol metabolism—also key risk factors in cardiovascular disease. LRH-1 has also been implicated as a tumor promoter in intestinal and pancreatic cancer. Overexpression of LRH-1 has been shown to promote invasiveness and metastasis, the usually lethal spread of the disease.
“LRH-1 has been implicated in the proliferation and metastasis of estrogen receptor-positive breast cancers and the more difficult to treat estrogen receptor-negative breast cancers,” said Research Associate Alex Corzo, the first author of the study. “This suggests that repressing LRH-1 could be useful in treating the more aggressive triple-negative breast cancer subtype where therapies are currently so limited.”
In fact, the study showed that levels of LHR-1 in a cell’s nucleus began to diminish four hours after treatment with SR1848, and the compound repressed specific target genes as early as two hours after administration.
Griffin noted that SR1848 also appears attractive as a potential therapeutic because of its lack of impact on cells that do not express LRH1, which could mean few potential side effects.
“It’s a novel mechanism that needs more study,” he said.
In addition to Griffin and Corzo, other authors of the study, “Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1s,” are Yelenis Mari, Mi Ra Chang, Tanya Khan, Dana Kuruvilla, Philippe Nuhant, Naresh Kumar, Graham M. West, Derek R. Duckett and William R. Roush of TSRI. See http://molpharm.aspetjournals.org/content/87/2/296.full
This work was supported by the Intramural Research Program of the National Institutes of Health’s (NIH) National Institute of Mental Health (U54-MH074404) and National Cancer Institute (R01-CA134873).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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