A protein called “liver receptor homolog-1,” or LRH-1, has been shown to play an important role in the progression of breast and pancreatic cancer. Scientists from Scripps Florida have identified a novel synthetic compound known as SR1848 that sharply reduces the activity and expression of this cancer-related protein.
Patrick Griffin is chair of The Scripps Research Institute Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida.
“Our study shows that SR1848 removes LRH-1 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.”
LRH-1 plays a crucial role in breast cancer through its regulation of genes involved in hormone synthesis and cholesterol metabolism – both 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.
Dr. Griffin noted that SR1848 also appears attractive as a potential therapeutic because of its lack of impact on cells that do not express LRH-1, which could mean few potential side effects. “It's a novel mechanism that needs more study,” he said.