Abstract
Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize. Clinically, TNBC remains a diagnosis of exclusion by the lack of hormone receptors (Estrogen Receptor (ER) and Progesterone Receptor (PR)) as well as the absence of overexpression and/or amplification of HER2. DNA methylation plays an important role in breast cancer carcinogenesis and TNBCs have a distinct DNA methylation profile characterized by marked hypomethylation and lower gains of methylations compared to all other subtypes. DNA methylation is regulated by the balance of DNA methylases (DNMTs) and DNA demethylases (TETs). Here, we review the roles of TETs as context-dependent tumor-suppressor genes and/or oncogenes in solid tumors, and we discuss the current understandings of the oncogenic role of TET1 and its therapeutic implications in TNBCs.
Highlights
Coriell Institute Research Department, Coriell Institute for Medical Research, Camden, NJ 08103, USA; Abstract: Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize
In multiple cancer cell lines and primary tumors, whole genome CpG methylation analysis showed that TET1, but not TET2 or TET3, was downregulated by promoter methylation compared to the normal controls
We highlight the role of DNA demethylases in TNBCs
Summary
Triple-negative breast cancer (TNBC) is a heterogenous disease that is genetically complex and is defined by lack of estrogen (ER)- and progesterone (PR)-receptor expression and the absence of overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2). Twenty years ago, using the microarray technique, four intrinsic breast cancer subtypes were identified (luminal A, luminal B, HER2-enriched, and basal-like) This was one of the first reports on basal-like breast tumors [4]. The four TNBC subclassifications are not yet routinely used in the clinical setting, these advances are important steppingstones to making this heterogenous group of cancer more amenable to new therapeutic insights and potentially to personalized medicine. These discoveries help shift the paradigm from what TNBC is, rather than to what it is not, and possibly to further sub-stratification. In this review we will present the functional role that epigenetic modifiers such as DNA demethylases play in driving this disease and how we envision their therapeutic potential
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