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Overabundance of protein expands breast cancer stem cells
Date:2/15/2011

earchers also tested an experimental drug called AZD6244, which specifically inhibits the MEK-ERK kinase cascade launched by RAF1. They found the drug eliminates EZH2-promoted breast cancer stem cells and blocks the formation of precancerous mammospheres.

"The drugs' inhibition of the breast tumor-initiating cells reveals a previously unidentified therapeutic effect for RAF1-ERK inhibitors to prevent breast cancer progression," Hung said. AZD6244 is being tested in multiple clinical trials, he noted, and it will be interesting to see whether the cancer-stem-cell-killing ability will be induced in those trials.

Hunting down a dangerous pathway

Breast cancer stem cells can be sorted from other primary cancer cells by the presence of the surface protein CD44 and low or absent CD24 in tumor cells.

The researchers found that high expression of EZH2 in breast cancer stem cells reduced the levels of the tumor suppressor RAD1 and correlated with high-grade tumors in a sample of 168 human breast cancer tumors. It also increased the number of tumor-initiating cells in culture.

EZH2 also is heavily expressed, and RAD1 diminished, by lack of oxygen in the tumor's environment, which causes activation of the HIF1a(alpha) protein. HIF1a(alpha), the researchers found, activates the EZH2 gene by binding to the gene's promoter region.

With RAD1 unable to repair damage, amplified RAF1 triggers the MEK-ERK--Catenin pathway, a well-known cancer promoting molecular pathway. The team showed EZH1 enhances this signaling pathway, which they found correlates with breast cancer progression.

In December, Hung and colleagues published a paper in Nature Cell Biology showing that the enzyme CDK1 shuts down EZH2.

Research was funded by grants from the National Cancer Institute, including those for MD Anderson's Specialized Program in Research Excellence (SPORE) for breast cancer and MD Anderson's cancer cente
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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