Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer.-猫眼课题宝

DOI：

10.1016/j.celrep.2015.05.011

发表时间：

2015-06

期刊：

Cell reports

影响因子：

8.8

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Ying Su;Ashim Subedee;Noga Bloushtain-Qimron;Virginia Savova;M. Krzystanek;Lewyn Li;A. Marusyk;D. Tabassum;Alexander Zak;Mary Jo Flacker;Mei Li;Jessica J Lin;Saraswati Sukumar;Hiromu Suzuki;Henry Long;Zoltán Szállási;Alexander Gimelbrant;R. Maruyama;K. Polyak

基底样乳腺肿瘤和管腔乳腺肿瘤具有不同的临床行为和分子特征，但其潜在机制尚不清楚。为了探究决定这些不同表型及其遗传模式的过程，我们生成了体细胞融合并进行了整合的遗传和表观遗传（DNA 甲基化和染色质）分析。我们发现，类基底性状通常占主导地位，并且很大程度上是由管腔转录因子的表观遗传抑制决定的。超级增强子的定义强调了管腔细胞中常见的核心程序，但与临床结果相关的基底样乳腺癌中存在高度异质性。我们还发现基底样细胞的蛋白质提取物足以诱导管腔到基底表型的转换，这意味着基底样自动调节回路的触发。我们确定 KDM6 可能是腔-基底融合所必需的，并且我们确定 EN1、TBX18 和 TCF4 作为腔-基底转换的候选转录调节因子。我们的研究结果强调了乳腺癌细胞显着的表观遗传可塑性。

Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined thatKDM6Amight be required for luminal-basal fusions, and we identifiedEN1,TBX18, andTCF4as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells.

Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer.

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