Aggressive cancer exploits MYC oncogene to amplify global gene activity

For a cancer patient, over-expression of the MYC oncogene is a bad omen.

Scientists have long known that in tumor cells, elevated levels of MYC's protein product, c-Myc, are associated with poor clinical outcomes, including increased rates of metastasis, recurrence, and mortality. Yet decades of research producing thousands of scientific papers on the subject have failed to consistently explain precisely how c-Myc exerts its effects across a broad range of cancer types. Until now, that is.

The prevailing theory emerging from this massive body of research has been that in tumor cells, c-Myc affects the expression of specific genes or sets of genes - that so-called Myc target genes are being selectively activated or repressed, leading to aberrant cellular behavior. Now, however, researchers in the lab of Whitehead Institute Member Richard Young are dispelling this commonly held notion, showing that elevated expression of c-Myc amplifies the activity of all expressed genes in tumor cells of multiple cancer types. It turns out that high levels of c-Myc send a tumor cell's gene expression program into overdrive. Transcription increases dramatically, allowing malignant cells to overwhelm factors that might normally hamper their growth and proliferation. This surprising finding, published in this week's issue of the journal Cell, provides a simple, elegant explanation for how a single protein can have such profound effect in so many and varied types of cancer. The newly revealed mechanism may also help scientists develop novel therapeutic approaches that disrupt c-Myc's activity.

"MYC is a key driver in most major cancers, but it has been notoriously difficult to drug," says Young, who is also a professor of biology at MIT. "Now that we know the mechanism by which c-Myc acts, we can go after the components of that mechanism as potential drug targets. This research creates an even stronger impetus to find a way to drug the thing."

One potential drawback to thwarting c-Myc's activity is the important role it plays in normal cell division. That role is so powerful that cells co-evolved an emergency death pathway to keep c-Myc expression in check. If c-Myc's production spins out of control in an otherwise normal cell, the cell immediately commits suicide through a process called apoptosis. But in cancer cells in which c-Myc is overproduced, this suicide pathway is compromised, allowing the cell to survive and proliferate.

Myc (c-Myc) is a regulator gene that codes for a transcription factor.

A mutated version of Myc is found in many cancers, which causes Myc to be constitutively (persistently) expressed. This leads to the unregulated expression of many genes, some of which are involved in cell proliferation and results in the formation of cancer. A common human translocation involving Myc is t(8;14) which is critical to the development of most cases of Burkitt's Lymphoma. A recent study demonstrated that temporary inhibition of Myc selectively kills mouse lung cancer cells, making it a potential cancer drug target.