DNMT3B7 Expression Promotes Tumor Progression to a More Aggressive Phenotype in Breast Cancer Cells
DNMT3B7 Expression Promotes Tumor Progression to a More Aggressive Phenotype in Breast Cancer Cells
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DOI：
10.1371/journal.pone.0117310
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发表时间：
2015-01-21
期刊：
影响因子：
3.7
通讯作者：
Raimondi, Stacey L.
中科院分区：
文献类型：
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作者：
Brambert, Patrick R.;Kelpsch, Daniel J.;Raimondi, Stacey L.
表观遗传变化（例如 DNA 甲基化）已被证明可促进乳腺癌进展。然而，癌细胞获得并维持异常 DNA 甲基化的机制尚不清楚。我们之前已经发现了 DNA 甲基转移酶 DNMT3B7 的异常剪接形式，它几乎在所有癌细胞系中表达，但在正常细胞中表达水平非常低。此外，与侵袭性较差的 MCF-7 细胞相比，侵袭性 MDA-MB-231 乳腺癌细胞表达的 DNMT3B7 水平升高，表明 DNMT3B7 可能在促进更具侵袭性的表型中发挥作用。使用从癌症基因组图谱收集的数据，我们发现与正常组织相比，乳腺癌患者组织中的 DNMT3B7 表达增加。为了确定 DNMT3B7 在乳腺癌细胞中发挥作用的机制，用 DNMT3B7 表达构建体稳定转染两种侵袭性较差的乳腺癌细胞系 MCF-7 和 T-47D。 DNMT3B7 的表达导致 E-钙粘蛋白的高甲基化和下调、β-连环蛋白的定位改变以及粘附周转、细胞增殖和贴壁依赖性生长增加。这项研究中提出的新结果表明 DNMT3B7 在乳腺癌进展到更具侵袭性的状态中发挥作用，并具有未来开发新疗法的潜力。
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 beta-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.