Public Release: 

Genetic mutation identified that results in aggressive, drug resistant, cancers

Memorial Sloan Kettering Cancer Center

New York, N.Y, January 18, 2001 -- What makes one patient's cancer more aggressive than another? Why does a patient's cancer develop resistance to a previously effective chemotherapy drug? A genetic mutation of the MAD2 protein may provide the answer to both of these questions.

Researchers at Memorial Sloan-Kettering Cancer Center have genetically engineered a mutation in the MAD2 gene in human cancer cells that eliminates a checkpoint essential to normal cell division. The resulting mutation made the tumor cells very genetically unstable, a characteristic long associated with more aggressive cancers. In addition, it rendered the cells resistant to taxanes. The result of the study, published in the January 18 issue of Nature, has implications for drug development and may provide a new marker for diagnosing the potential aggressiveness of tumors.

In 1996, Drs. Robert Benezra and Yong Li of Memorial Sloan-Kettering Cancer Center identified MAD2, a member of a class of proteins referred to as mitotic checkpoint proteins.

These ensure the equal distribution of chromosomes to the two daughter cells during cell division. The loss of this checkpoint results in a form of chromosome instability in which whole chromosomes can be lost or gained. Cancers that exhibit this type of chromosome instability are usually more aggressive and have a poor prognosis. Correlations between chromosome instability and the loss of the mitotic checkpoint have been identified in human colon cancer cell lines. However, there was previously no evidence providing a direct relationship between these two phenomena. Now, researchers in the Benezra laboratory have found that the loss of MAD2 in a genetically stable cancer cell line created chromosome instability.

"When we took a particularly stable human colon carcinoma cell line and genetically engineered the loss of one copy of the MAD2 gene, we were able to visualize the cell's chromosomes falling apart prematurely during cell division by using a simple test," said Loren Michel, MD, the study's lead author. "Although the loss of one copy of MAD2 caused only subtle decreases in the amount of MAD2 protein levels, it had a great impact on the cell's genetic behavior. The tumors became highly genomically unstable and continued to grow even in the presence of chemotherapy drugs in the taxane family. Our results suggest that developing a similar test to detect the changes in this genetic pathway in human cancers could be used to predict disease progression."

Taking their findings one step further, they found that the identical genetic mutation that had such a dramatic effect on a pre-existing tumor cell could also contribute to the initiation of cancerous tumors in mice. "Mice with complete absence of MAD2 protein die during embryonic development. We introduced a mutation that inactivated just one copy of the MAD2 gene in mice and this resulted in cancer," explained Vasco Liberal, a study author from Memorial Sloan-Kettering. "Uniquely, this mutation resulted in a high frequency of lung carcinomas despite the fact that these genes are found in every cell of the body and the disease is extremely rare in most mice. Why the lung tissue is specifically affected is unknown but it does show that disruption of this process participates in the development of cancer. Interestingly in humans, low levels of MAD2 have been observed in breast tumor cell lines."

The researchers also found that small changes in the MAD2 protein level result in a partial loss of the mitotic checkpoint. "When the cell was missing half a dose, it became resistant to taxane drugs. This was a surprise since the yeast results suggested the exact opposite," said Robert Benezra, PhD., senior author of the study and head of the Molecular Mechanisms of Differentiation Laboratory at Memorial Sloan-Kettering. "This could have implications as to why a cancer cell suddenly develops drug resistance and needs further investigation."


Also participating in this study were V.V.V.S. Murty, PhD. and Anupam Chatterjee, PhD., Columbia Presbyterian College of Physicians and Surgeons; Boris Pasche, PhD., Northwestern University Medical School; Max Dobles, PhD and Peter K. Sorger, PhD., Massachusetts Institute of Technology; and Regina Kirchwegger, PhD. of Memorial Sloan-Kettering Cancer Center. The work was supported by a grant from the National Institutes of Health.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.