"Genetic mutations do not drive this mechanism," said Alana Welm, PhD, senior author of the study, associate professor in the Department of Oncological Sciences, and an investigator at Huntsman Cancer Institute. "Instead, it's improper regulation of when genes turn on and off."
The new discovery focuses on a protein called RON kinase (RON), which signals some areas of tumor cell DNA to become active. Normally, RON operates mostly during embryonic development and is not highly expressed in healthy adults. But in about 50 percent of breast cancer cases, RON becomes re-expressed and reprograms genes responsible for metastasis, making them active.
"If there's an entire program in the tumor cell that's important for metastasis, blocking one small part of that program, for example, the action of a single gene, will probably not be an effective strategy," said Welm. "But if you could find a way to turn off the entire program, you're more likely to have the desired effect. We found that inhibiting RON turns off the entire metastasis program in these tumor cells.
"No one has ever described a specific pathway driving this kind of reprogramming in metastasis, much less a way to therapeutically block it,' Welm added. "Also, RON has not previously been known to be involved in reprogramming gene expression."
Future work will include investigating the potential of detecting the RON-dependent program in tumor cells as a way to identify patients that are more likely to develop metastases and as a predictor of therapeutic response to drugs that inhibit RON.
The article's co-authors include Stéphanie Cunha, Yi-Chun Lin, Elizabeth Goossen, and Christa DeVette from HCI, and Mark Albertella, Mark Mulvihill, and Stuart Thomson of OSI/Astellas. The work was funded by the DOD Breast Cancer Research Program Era of Hope Scholar Award, a Susan G. Komen for the Cure Career Catalyst Award, and Huntsman Cancer Foundation. Research reported in this publication utilized HCI's Microarray and Genomic Analysis Shared Resource and was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014.
The mission of Huntsman Cancer Institute (HCI) at The University of Utah is to understand cancer from its beginnings, to use that knowledge in the creation and improvement of cancer treatments, to relieve the suffering of cancer patients, and to provide education about cancer risk, prevention, and care. HCI is a National Cancer Institute-designated cancer center, which means that it meets the highest national standards for world-class, state-of-the-art programs in multidisciplinary cancer research and receives support for its scientific endeavors. HCI is also a member of the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of the world's leading cancer centers dedicated to improving the quality and effectiveness of care provided to patients with cancer.
Linda Aagard | EurekAlert!
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