Features | Partner Sites | Information | LinkXpress
Sign In
JIB
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING

Blocking RON Shuts Down Breast Cancer Metastasis

By BiotechDaily International staff writers
Posted on 16 Jan 2014
A recent paper suggested that initiation of breast cancer metastasis did not depend on a specific genetic mutation but rather on improper regulation of molecular pathways that control activation and inactivation of certain critical genes.

Investigators at the University of Utah (Salt Lake City, USA) focused their research on the protein product of the RON gene, known as macrophage stimulating 1-receptor (MST1R), a member of the Met family of receptor tyrosine kinases. The biological activity of RON was mediated by binding of its extracellular ligand, macrophage-stimulating protein (MSP), and the protein macrophage stimulating 1 (MST1). Binding of MSP activated RON and led to cellular growth, motility, and invasion. Recent studies have documented RON overexpression in a variety of human cancers including those of the breast, colon, liver, pancreas, and bladder, which often correlate with poor outcome. Moreover, clinical studies have shown that RON overexpression is associated with metastasis and worse patient outcomes.

In the current study, published in the January 2, 2014, online edition of the journal Cell Reports, the investigators showed that the RON/MSP pathway enhanced metastasis of breast cancer xenografts by reprogramming DNA methylation at specific target genes.

RON/MSP-initiated differential-DNA methylation was found to be the result of upregulation of the enzyme MBD4 (methyl-CpG binding domain protein 4), a thymine DNA glycosylase. MBD4 bound specifically to methylated DNA via an MBD domain at the N-terminus that functioned both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that was involved in DNA repair.

Knockdown of MBD4 in RON/MSP-expressing breast cancer cells or inhibition of the glycosylase catalytic residue of MBD4 reversed the DNA methylation pattern on specific loci and blocked metastasis.

“Genetic mutations do not drive this mechanism,” said senior author Dr. Alana Welm, associate professor of oncological sciences at the University of Utah. “Instead, it is improper regulation of when genes turn on and off. No one has ever described a specific pathway driving this kind of reprogramming in metastasis, much less a way to therapeutically block it. Also, RON has not previously been known to be involved in reprogramming gene expression.”

“If there is an entire program in the tumor cell that is 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 Dr. Welm. “But if you could find a way to turn off the entire program, you are more likely to have the desired effect. We found that inhibiting RON turns off the entire metastasis program in these tumor cells.

Related Links:

University of Utah



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: The European Commission has approved the use of Avastin combined with chemotherapy as a treatment for women with recurrent ovarian cancer (Photo courtesy of Genentech).

Drug for Treatment of Platinum Resistant Recurrent Ovarian Cancer Approved for Use in Europe

For the first time in more than 15 years the European Commission (EC) has approved a new therapeutic option for the most difficult to treat form of ovarian cancer. Ovarian cancer causes more deaths... Read more

Therapeutics

view channel
Image: This type of electronic pacemaker could become obsolete if induction of biological pacemaker cells by gene therapy proves successful (Photo courtesy of Wikimedia Commons).

Gene Therapy Induces Functional Pacemaker Cells in Pig Heart Failure Model

Cardiovascular disease researchers working with a porcine heart failure model have demonstrated the practicality of using gene therapy to replace implanted electronic pacemakers to regulate heartbeat.... Read more

Lab Technologies

view channel
Image: The DrySyn MULTI converts any standard hotplate stirrer into a high performance reaction block (Photo courtesy of Asynt).

New Reaction Vessel Heating System Is Cleaner and Safer

Biotech and other life science researchers can create a safer, cleaner, and more efficient working environment in their laboratories by switching from oil bath-based heating of reaction vessels to a new... Read more

Business

view channel

Global Computational Biology Sector Expected to Reach over USD 4 Billion by 2020

The global market for computational biology is expected to reach USD 4.285 billion by 2020 growing at a compound annual growth rate (CAGR) of 21.1%, according to new market research. Steady surge in the usage and application of computational biology for bioinformatics R&D programs designed for sequencing genomes... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.