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Epigenetics. 2014 Feb;9(2):297-307. doi: 10.4161/epi.27111. Epub 2013 Nov 13.

High-density array analysis of DNA methylation in Tamoxifen-resistant breast cancer cell lines.

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Molecular & Cellular Biology Graduate Program; Department of Veterinary & Animal Sciences; University of Massachusetts; Amherst, MA USA.
Department of Sociology; University of South Carolina; Columbia, SC USA.
Center for Cancer Research; National Institutes of Health; Bethesda, MD USA.
Wadsworth Center; Albany, NY USA.


Roughly two-thirds of all breast cancers are ERα-positive and can be treated with the antiestrogen, Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 y. Aberrant DNA methylation, an epigenetic mechanism that alters gene expression in cancer, is thought to play a role in this resistance. To develop an understanding of Tamoxifen-resistance and identify novel pathways and targets of aberrant methylation, DNA from MCF-7 breast cancer cells and Tamoxifen-resistant derivatives, TMX2-11 and TMX2-28, were analyzed using the Illumina HumanMethylation450 BeadChip. Normalizing against MCF-7 values, ERα-positive TMX2-11 had 4000 hypermethylated sites and ERα-negative TMX2-28 had over 33 000. Analysis of CpG sites altered in both TMX2-11 and TMX2-28 revealed that the Tamoxifen-resistant cell lines share 3000 hypermethylated and 200 hypomethylated CpGs. ZNF350 and MAGED1, two genes hypermethylated in both cell lines, were examined in greater detail. Treatment with 5-aza-2ꞌdeoxycitidine caused a significant reduction in promoter methylation of both ZNF350 and MAGED1 and a corresponding increase in expression in TMX2-28. A similar relationship between methylation and expression was not detected in TMX2-11. Our findings are indicative of the variable responses to methylation-targeted breast cancer therapy and highlight the need for biomarkers that accurately predict treatment outcome.


Breast Cancer; Estrogen Receptor; HumanMethylation450 BeadChip; MAGED1; Tamoxifen Resistance; ZNF350; methylation

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