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From OncoLog, April-May 2011, Vol. 56, No. 4-5

Graphic: In Brief header

Study Reveals How EZH2 Protein Promotes Breast Tumor–Initiating Cell Growth

Researchers from MD Anderson recently discovered the mechanism by which the EZH2 protein, which is essential to normal stem cell renewal, also promotes an increase in the number of breast tumor–initiating cells. The researchers also found that two drugs block this mechanism and the subsequent increase in the number of breast tumor–initiating cells.

Overexpression of the EZH2 protein had previously been linked to breast cancer progression, but the molecular details of that connection were unknown, according to Mien-Chie Hung, Ph.D., chair of and a professor in the Department of Molecular and Cellular Oncology and the senior author of the study’s report in the January 18 issue of Cancer Cell.

The researchers found that a hypoxic tumor microenvironment can initiate a molecular cascade that fosters the self renewal, survival, and growth of breast tumor–initiating cells. First, the lack of oxygen stimulates the hypoxia-inducible factor 1a protein, which in turn binds to the promotor region of the EZH2 gene and causes EZH2 overexpression. The abundant EZH2 then slows the production of RAD51, an important tumor suppressor protein involved in DNA damage repair. As DNA damage and chromosomal aberrations mount in the absence of RAD51, the production of protein kinase RAF1 is amplified, triggering the MEK-ERK-β-catenin signaling pathway, which in turn promotes the increase of breast tumor–initiating cells and cancer progression.

To determine which drugs might block this cascade, the team tested five anticancer drugs—sorafenib, imatinib, lapatinib, paclitaxel, and the small molecule RITA (reactivation of p53 and induction of tumor cell apoptosis)—in human primary breast cancer cells and in a xenograft mouse model of human tumor cells. Sorafenib, an inhibitor or RAF1 and other targets, eliminated more breast tumor-initiating cells and blocked tumor formation more effectively than the other four drugs.

To test whether sorafenib’s effectiveness was the result of its inhibiting RAF1 or a different target, the researchers then investigated AZD6244, an experimental drug that specifically inhibits the MEK-ERK kinase cascade launched by RAF1. AZD6244 eliminated EZH2-promoted breast tumor–initiating cells and blocked the formation of xenograft tumors and mammospheres, cell spheroids originated from self-renewing tumor-initiating cells.

Dr. Hung said the drugs’ inhibition of the breast tumor–initiating cells revealed the prevention of breast cancer progression as a previously unidentified therapeutic effect for RAF1-ERK inhibitors.

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