JARID1B is a luminal lineage-driving oncogene in breast cancer.
JARID1B is a luminal lineage-driving oncogene in breast cancer.
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DOI：
10.1016/j.ccr.2014.04.024
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发表时间：
2014-06-16
期刊：
影响因子：
50.3
通讯作者：
Polyak K
中科院分区：
文献类型：
--
作者：
Yamamoto S;Wu Z;Russnes HG;Takagi S;Peluffo G;Vaske C;Zhao X;Moen Vollan HK;Maruyama R;Ekram MB;Sun H;Kim JH;Carver K;Zucca M;Feng J;Almendro V;Bessarabova M;Rueda OM;Nikolsky Y;Caldas C;Liu XS;Polyak K
组蛋白修饰酶的反复突变在肿瘤发生中起关键作用，但其功能相关性在很大程度上是未知的。在这里，我们发现编码组蛋白H3赖氨酸4 （H3K4）去甲基化酶的JARID1B在腔内乳腺肿瘤中经常被扩增和过表达，基底样乳腺癌的体细胞突变导致独特的染色质结合和腔内表达和剪接模式的获得。在管腔细胞中下调JARID1B可诱导基础基因表达和生长停滞，这可通过TGFβ通路抑制剂来挽救。综合的JARID1B染色质结合、H3K4甲基化和表达谱表明，JARID1B在腔细胞特异性表达程序中具有关键功能。高腔内JARID1B活性与激素受体阳性乳腺肿瘤患者预后不良相关。
Recurrent mutations in histone modifying enzymes imply key roles in tumorigenesis yet their functional relevance is largely unknown. Here we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGFβ pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor positive breast tumors.