Researchers from the Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabrain Barcelona, Spain, have identified a protein that they believe may help predict breast cancer prognosis. According to the researchers, this finding may potentially relieve thousands of women at low risk for breast cancer from having to undergo painful, often debilitating therapies, while insuring the most successful treatments for those at high risk. The research was published ahead of print in the August 5, 2013 online edition of the Journal Molecular and Cellular Biology, a publication of the American Society for Microbiology (ASM).[1]

Using bioinformatics techniques, the authors showed that the levels of expression of some 1,200 genes that are directly controlled by the enzyme called EZH2 (enhancer of zeste homolog 2) which correlates with the aggressiveness of breast cancer cases.

…Stratification will enable clinicians to accurately predict breast cancer progression…

The pathogenic role of EZH2, a member of the polycomb-group (PcG) family, has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression. But, until now, little was known about relation of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. In this study, which was supported by the Spanish Ministry of Science and Technology and the U.S. National Institutes of Health (NIH), the researchers found that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding breast cancer patients can, independen of known cancer gene signatures, bestratified into two groups – agood and a poor prognostic group.

“The analysis pipeline that we developed will be useful for stratification of breast cancer patients,” Elizaveta Benevolenskaya from the Department of Biochemistry and Molecular Genetics of the University of Illinois at Chicago(UIC), one of the researcher and a co-author of the study, said. “Stratification will enable clinicians to accurately predict breast cancer progression. The level of expression of a subgroup of EZH2-bound genes could have further predictive value, indicating, for example, that a specific treatment regime is needed.”

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Breast cancer
In the study, Benevolenskaya and her collaborators generated breast cancer cells in which they could dampen expression of EZH2 using a technique called RNA inhibition. Inhibiting EZH2 expression reactivated the genes this enzyme controls, which resulted in less aggressive cancer phenotypes.

“In addition to predicting aggressiveness,” Benevolenskaya explains, “Small molecule inhibitors of EZH2, which have recently become available, could be developed as therapeutic drugs for the treatment of breast cancer. The advantage of small molecules is that they are cheaper to manufacture, and generally can be taken by mouth, unlike larger molecules, which must be given by injection.”

Other cancers
Besides breast cancer, EZH2 overexpression appears to be associated with a worse prognosis in prostate, endometrial, and melanoma tumors. Unrelated studies also show that EZH2 expression is high in pediatric glioblastoma (GBM).[2] “The computational analysis used in our research could also be helpful for predicting the aggressiveness of these and other cancers,” Benevolenskaya noted.

For more information:
[1] Jene-Sanz A, Renta V, Vilkova AV, Khramtsova GF, Khramtsov AI, Olopade OI, Lopez-Bigas N, Benevolenskaya EV. Expression of Polycomb targets predicts breast cancer prognosis.Mol Cell Biol. 2013 Aug 5. [Epub ahead of print][Article][PubMed]
[2] Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT, Heguy A, et al. Evaluation of Histone 3 Lysine 27 Trimethylation (H3K27me3) and Enhancer of Zest 2 (EZH2) in Pediatric Glial and Glioneuronal Tumors Shows Decreased H3K27me3 in H3F3A K27M Mutant Glioblastomas.Brain Pathol. 2013 Sep;23(5):558-64. doi: 10.1111/bpa.12042. Epub 2013 Mar 6 [Article][PubMed]

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