"We have greatly expanded our knowledge of the Nod1 pathway beyond its known role in response to infection," said Richard J. Ulevitch, Ph.D. Ulevitch, who led the study, is a professor and chairman of the Scripps Research Department of Immunology. "These unexpected findings offer the first real evidence that this pathway may regulate tumor growth and suggest a potentially new mechanism for controlling this type of breast cancer. Unraveling the intricate mechanisms of this previously unknown pathway opens up the potential for future development of novel therapeutics, and will hopefully stimulate researchers to take a fresh look at the Nod1 protein."
In the study, researchers looked at a number of biological processes where Nod1-dependent apoptotic (programmed cell death) pathways were a critical component, including the regulation of tumor cell growth where the failure of malignant cells to undergo cell death led to tumorigenesis. Cells derived from the human breast cancer epithelial cell line MCF-7 – the cellular model for estrogen sensitive breast cancer tumors – were used to induce tumor growth in severe combined immunodeficiency (SCID) mice. An over-expression of Nod1 in MCF-7 cells resulted in the inhibition of estrogen-dependent tumor growth in the SCID mice and a reduction of estrogen-induced proliferative responses in vitro. Moreover, scientists found that the tumors diminished rapidly in these mice, becoming virtually undetectable by the end of the experiment.
In MCF-7 cells where Nod1 was absent, the tumors flourished. In addition, there was an increased sensitivity to estrogen-induced cell proliferation and a failure to undergo Nod1-dependent apoptosis in vitro.
Taking these initial findings one step further, researchers implanted estrogen pellets in the SCID mice to accelerate tumorigenesis. In those mice receiving Nod1 cell lines tumor growth did not occur even in the presence of estrogen pellets, indicating that Nod1 acts as an effective cellular brake on estrogen-dependent tumor growth. In addition, the presence of Nod1 reduced the expression of the naturally occurring estrogen receptor in vitro, further indication that the protein mediates the sensitivity of hormone-dependent breast cancer cells to tumorigenesis.
"While still preliminary, our data adds another critical function to Nod1," Ulevitch said, "namely its ability to regulate the growth of estrogen-sensitive tumors formed by specific cell lines in immune deficient mice. The evidence uncovered in this study provides new insights into the physiological functions of Nod1 and supports our contention that there is a clear link between Nod1 and estrogen sensitivity in these cells. Our future studies will assess the relationship between the pathway uncovered in breast cancer and other hormone sensitive malignancies. Those studies may help in the development of new therapeutic approaches with the potential to stabilize or even eradicate hormone-sensitive tumors."
Co-authors of the study included Jean da Silva Correia, Yvonne Miranda, Nikki Austin-Brown, Jenny Hsu, John Mathison, Rong Xiang, and Jiahuai Han, all of The Scripps Research Institute Department of Immunology and; Huamin Zhou and Qinxi Li from Xiamen University School of Life Sciences, Fujian, China. Funding for the study was provided by the National Institutes of Health (NIH) and Novartis Pharmaceuticals.
About The Scripps Research Institute
The Scripps Research Institute, headquartered in La Jolla, California, in 15 buildings on 10 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.
Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.
Journal
Proceedings of the National Academy of Sciences