Blocking RON Shuts Down Breast Cancer Metastasis

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.

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