DNMT3B7 Expression Promotes Tumor Progression to a More Aggressive Phenotype in Breast Cancer Cells

Abstract

Epigenetic changes, such as DNA methylation, have been shown to promote breast cancer progression. However, the mechanism by which cancer cells acquire and maintain abnormal DNA methylation is not well understood. We have previously identified an aberrant splice form of a DNA methyltransferase, DNMT3B7, expressed in virtually all cancer cell lines but at very low levels in normal cells. Furthermore, aggressive MDA-MB-231 breast cancer cells have been shown to express increased levels of DNMT3B7 compared to poorly invasive MCF-7 cells, indicating that DNMT3B7 may have a role in promoting a more invasive phenotype. Using data gathered from The Cancer Genome Atlas, we show that DNMT3B7 expression is increased in breast cancer patient tissues compared to normal tissue. To determine the mechanism by which DNMT3B7 was functioning in breast cancer cells, two poorly invasive breast cancer cell lines, MCF-7 and T-47D, were stably transfected with a DNMT3B7 expression construct. Expression of DNMT3B7 led to hypermethylation and down-regulation of E-cadherin, altered localization of β-catenin, as well as increased adhesion turnover, cell proliferation, and anchorage-independent growth. The novel results presented in this study suggest a role for DNMT3B7 in the progression of breast cancer to a more aggressive state and the potential for future development of novel therapeutics.

HDAC inhibitor misprocesses bantam oncomiRNA, but stimulates hid induced apoptotic pathway

“…Apoptosis contributes to pattern development mainly by removing excess cell population and fine tuning developing structures. In normal cells, apoptosis gets initiated in response to developmental needs, whereas in cancer cells oncogenic signals lead to rapid and uncontrolled cell proliferation resulting in abnormal tissue growth 1 2 3 4 . How these cellular processes are coordinated during development is poorly understood and still remains a challenging task.…”

The role of aberrant DNMT3Bs in tumor progression – a review

“…To further support this hypothesis, Brambert and colleagues noted increased cell proliferation, cell adhesion turnover, and anchorage-independent growth in cells transfected with DNMT3B7 -all indicators of a more aggressive phenotype [20] . These results correlate well with previous data indicating higher expression of DNMT3B7 in aggressive MDA-MB-231 cells, compared to the poorly aggressive MCF-7 line [14] .…”

“…While these results suggest a correlation between DNMT3B7 and a more aggressive breast cancer phenotype, Brambert and colleagues transfected DNMT3B7 into poorly aggressive breast cancer cell lines to validate this hypothesis. DNMT3B7 transfection into the poorly aggressive breast cancer cell lines, MCF-7 and T-47D, resulted in phenotype alterations that parallel phenotypes characteristic of the more aggressive breast cancer cell line, MDA-MB-231 [20] . More specifically, hypermethylation and downregulation of E-cadherin was observed in the transfected cell lines.…”

“…Clinical data separated based on stage of breast cancer indicated increased prevalence of DNMT3B7 in stages II-IV compared to stage I. In addition, data separated by molecular subtype and analyzed in the BRCA clinical database indicated increased expression of DNMT3B7 in triple negative/basal-like and HER2 type patients compared to Luminal A and Luminal B subtypes [20] . It is well documented that patients with triple negative/basal-like and HER2-like cancer diagnoses have an aggressive form of cancer that is difficult to treat compared to patients diagnosed with luminal breast cancer [1] .…”

“…Previous data have suggested the role of the aberrant transcript, DNMT3B7, in altering methylation and gene expression in cancer cells [14,20] . In order to characterize the role of DNMT3B7 in human neuroblastoma, Ostler and colleagues examined DNA methylation, gene expression, and phenotype [26] .…”