Editors' ChoiceCancer

An Epigenetic Road to Genome Instability

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Science Translational Medicine  26 Jan 2011:
Vol. 3, Issue 67, pp. 67ec10
DOI: 10.1126/scitranslmed.3002145

Although the importance of genetic changes in many processes has been well appreciated for decades, more recent work demonstrates that epigenetic changes also play a key role, including in the biology of stem cells and in cancer. Indeed, there is increasing evidence that many epigenetic and genetic changes cooperate to promote transformation of so-called cancer stem cells. In a new study, Chang et al. determined that a key enzyme involved in epigenetic alterations, the histone methyltransferase EZH2, triggers genomic instability and subsequent activation of oncogenic signaling pathways in breast tumor initiating cells (BTICs), a putative breast cancer stem cell population.

The authors first determined that EZH2 is highly expressed in BTICs and that EZH2 overexpression in primary breast tumor cells leads to an increased number of BTICs. These BTICs were genetically unstable and had enhanced self-renewal capacity, and these effects were dependent on EZH2’s repression of the DNA repair gene RAD51. Indeed, simultaneous overexpression of EZH2 and RAD51 abrogated EZH2’s effects.

To determine the downstream pathways that were triggered by loss of RAD51 function in BTICs, the authors next analyzed results of protein arrays. After EZH2 overexpression or suppression of RAD51 with RNA interference, RAF1 was the most highly expressed protein in BTICs, an effect caused by genomic instability and RAF1 gene amplifications. RAF1 overexpression led to activation of downstream RAF1 oncogenic pathways [involving the extracellular signal–regulated kinase (ERK) and β-catenin] and enhanced proliferation. Lastly, the authors demonstrated that treatment of BTICs that harbored these RAF1 amplifications with sorafenib (a RAF1 inhibitor approved by the U.S. Food and Drug Administration) or with an inhibitor of ERK potently reduced BTIC survival.

These results demonstrate the complexity of tumors and how epigenetic events can drive genomic instability and up-regulation of oncogenic signaling pathways in cancer stem cell populations. The next question is whether RAF or ERK inhibitors will have additive effects with standard breast cancer treatments and increase cure rates rather than merely increase toxicity.

C.-J. Chang et al., EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell 19, 86–100 (2011). [Full Text]

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