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Epithelial Progeny of Estrogen-Exposed Breast Progenitor Cells Display a Cancer-like Methylome

¹ Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ² Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; ³ Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; ⁴ Sequenom, Inc., San Diego, California; ⁵ Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana; ⁶ Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; and ⁷ Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Taiwan, Republic of China

Requests for reprints: Tim H-M. Huang, Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. Phone: 614-688-8277; Fax: 614-292-5995; E-mail: tim.huang{at}osumc.edu.

Key Words: estrogen • breast progenitor cells • methylome • hypermethylation

Estrogen imprinting is used to describe a phenomenon in which early developmental exposure to endocrine disruptors increases breast cancer risk later in adult life. We propose that long-lived, self-regenerating stem and progenitor cells are more susceptible to the exposure injury than terminally differentiated epithelial cells in the breast duct. Mammospheres, containing enriched breast progenitors, were used as an exposure system to simulate this imprinting phenomenon in vitro. Using MeDIP-chip, a methylation microarray screening method, we found that 0.5% (120 loci) of human CpG islands were hypermethylated in epithelial cells derived from estrogen-exposed progenitors compared with the non–estrogen-exposed control cells. This epigenetic event may lead to progressive silencing of tumor suppressor genes, including RUNX3, in these epithelial cells, which also occurred in primary breast tumors. Furthermore, normal tissue in close proximity to the tumor site also displayed RUNX3 hypermethylation, suggesting that this aberrant event occurs in early breast carcinogenesis. The high prevalence of estrogen-induced epigenetic changes in primary tumors and the surrounding histologically normal tissues provides the first empirical link between estrogen injury of breast stem/progenitor cells and carcinogenesis. This finding also offers a mechanistic explanation as to why a tumor suppressor gene, such as RUNX3, can be heritably silenced by epigenetic mechanisms in breast cancer. [Cancer Res 2008;68(6):1786–96]

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