title: Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome.
abstract: 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.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.forename: Aedín C
authors.initials: AC
authors.lastname: Culhane
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.forename: Chinnambally R
authors.initials: CR
authors.lastname: Venkataramu
authors.forename: Mathias
authors.initials: M
authors.lastname: Ehrich
authors.forename: Aejaz
authors.initials: A
authors.lastname: Nasir
authors.forename: Benjamin A T
authors.initials: BA
authors.lastname: Rodriguez
authors.forename: Joseph
authors.initials: J
authors.lastname: Liu
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
mesh_terms: D000293:Adolescent; D000328:Adult; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004847:Epithelial Cells / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D047628:Estrogen Receptor alpha; C493729:Runx3 protein, human; D004958:Estradiol