title: Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation.
abstract: A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes - basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan-Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599 USA; UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 USA. Electronic address: droll@esquaredcommunications.net.
authors.forename: J Devon
authors.initials: JD
authors.lastname: Roll
authors.forename: Ashley G
authors.initials: AG
authors.lastname: Rivenbark
authors.forename: Rupninder
authors.initials: R
authors.lastname: Sandhu
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Wendell D
authors.initials: WD
authors.lastname: Jones
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.forename: Chad A
authors.initials: CA
authors.lastname: Livasy
authors.forename: William B
authors.initials: WB
authors.lastname: Coleman
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
keywords: Aberrant DNA hypermethylation; Basal-like breast cancer; Claudin-low breast cancer; DNA methyltransferase; DNMT; EMT; ER; HER2; PR; TIC; TMI; Triple-negative breast cancer; epithelial-to-mesenchymal transition; estrogen receptor; gene encoding the epidermal growth factor receptor 2; miR; microRNA; progesterone receptor; total methylation index; tumor initiating cell