Faculty Member Robert Benezra

A team of scientists led by Memorial Sloan-Kettering Cancer Center cancer biologist Robert Benezra has revealed new insights into the mechanism of tumor formation by boosting levels of the Mad2 gene in mice. The study was published in the January 15 issue of Cancer Cell. [PubMed Abstract]

Mad2 is an essential component of the spindle checkpoint -- a proofreading mechanism in cell division that ensures the proper separation of copied chromosomes, which carry genetic information into the next generation of cells. Mad2 levels increase when the tumor suppressor gene Rb is lost or mutated but unlike other cancer-causing genes Mad2 itself is rarely mutated. Increases in Mad2 are associated with malfunctions that lead to a variety of chromosomal defects -- the type of defects frequently seen in human cancers.

One of these chromosomal problems is called aneuploidy, which is a gain or loss of chromosomes. Until now, it was unclear whether aneuploidy was a cause or consequence of cancer. Research fellow Rocio Sotillo, a member of Dr. Benezra's laboratory, demonstrated that mice genetically engineered to overexpress Mad2 developed chromosomal instability and aneuploidy. High Mad2 levels also resulted in the formation of aggressive tumors in multiple organs. These tumors likely result from changes in as-yet-unidentified cancer-causing genes that are altered as a consequence of the observed chromosome instability.

Moreover, switching off cancer-causing genes usually causes tumors to shrink. But when Mad2 was switched off in mice, tumors kept growing.

"The fact that we can turn Mad2 off and still see maintenance of the tumors is consistent with the notion that aneuploidy was the main driving effect," explained Dr. Benezra on the role of Mad2 in cancer. "These findings also raise the possibility that Mad2 is a major mediator of cancer formation caused by Rb loss."