Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation.
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.
['Roll|J Devon|JD|', 'Rivenbark|Ashley G|AG|', 'Sandhu|Rupninder|R|', 'Parker|Joel S|JS|', 'Jones|Wendell D|WD|', 'Carey|Lisa A|LA|', 'Livasy|Chad A|CA|', 'Coleman|William B|WB|']
D014408:Biomarkers, Tumor D001940:Breast D019175:DNA Methylation D057890:Epigenomics D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D009364:Neoplasm Recurrence, Local D011379:Prognosis D011401:Promoter Regions, Genetic D018719:Receptor, ErbB-2 D011960:Receptors, Estrogen D011980:Receptors, Progesterone D015996:Survival Rate D064726:Triple Negative Breast Neoplasms
Triple-negative breast cancer Claudin-low breast cancer Aberrant DNA hypermethylation DNA methyltransferase Basal-like breast cancer DNMT EMT ER HER2 PR TIC TMI epithelial-to-mesenchymal transition estrogen receptor gene encoding the epidermal growth factor receptor 2 miR microRNA progesterone receptor total methylation index tumor initiating cell