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[Cancer Research 64, 8184-8192, November 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer

Yu-Wei Leu1, Pearlly S. Yan1, Meiyun Fan2,3, Victor X. Jin1, Joseph C. Liu1, Edward M. Curran4, Wade V. Welshons4, Susan H. Wei1, Ramana V. Davuluri1, Christoph Plass1, Kenneth P. Nephew2,3 and Tim H-M. Huang1

1 Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; 2 Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana; 3 Department of Cellular and Integrative Physiology and Obstetrics and Genecology, Indiana University Cancer Center, Indianapolis, Indiana; and 4 Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, Missouri

Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) {alpha} signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ER{alpha} target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ER{alpha} signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ER{alpha} targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ER{alpha} target genes, providing new direction for research in this classical signaling pathway.




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