MLL3 is a de novo cause of endocrine therapy resistance.
MLL3 is a de novo cause of endocrine therapy resistance.
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DOI：
10.1002/cam4.4285
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发表时间：
2021-11
期刊：
影响因子：
4
通讯作者：
Stricker T
中科院分区：
文献类型：
--
作者：
Stauffer KM;Elion DL;Cook RS;Stricker T
癌症重测序研究表明表观遗传酶是复发性突变的共同靶点。单甲基转移酶MLL3是雌激素受体阳性乳腺癌中最常发生突变的酶之一。MLL3产生的H3K4me1标记可以定义增强子。在ER+乳腺癌中，ERα基因组结合位点主要是远端增强子。因此，我们假设MLL3突变会改变ERα的基因组结合和转录调节活性。我们研究了在MLL3/PIK3CA WT ER阳性乳腺癌细胞系中敲除MLL3的基因组后果。MLL3的缺失导致整个基因组中H3K4me1的大量缺失，以及ERα结合位点的基因组位置的转移，这伴随着乳腺癌转录组的重组。MLL3 KD细胞中ERα结合位点的基因集富集分析确定了内分泌治疗耐药条件，我们发现MLL3 KD细胞对他莫昔芬和氟维司汀耐药。许多差异表达基因是由H3K4me1沉积和ERα结合的一小部分新位置控制的，这表明功能性MLL3的缺失导致了必需基因的新转录调控。RNA - seq和ChIP - seq数据的基序分析强调SP1是MLL3 KD细胞中的关键转录因子。在MLL3 KD上显示ERα结合缺失的差异表达基因也会增加SP1的结合。我们的数据显示功能性MLL3的减少会导致内分泌治疗抵抗。这突出了在决定治疗计划之前，在初始切除时对患者肿瘤样本进行MLL3突变基因分型的重要性。MLL3是ER+乳腺癌患者中第6个最常见的突变基因，但其在乳腺癌中调节ERα转录活性的作用尚不清楚。我们的数据表明，MLL3的突变通过改变基因组增强子和ERα结合景观导致转录组改变，从而导致内分泌治疗耐药性，因此在决定治疗过程之前应该进行基因分型。
Cancer resequencing studies have revealed epigenetic enzymes as common targets for recurrent mutations. The monomethyltransferase MLL3 is among the most recurrently mutated enzymes in ER+ breast cancer. The H3K4me1 marks created by MLL3 can define enhancers. In ER+ breast cancer, ERα genome‐binding sites are primarily distal enhancers. Thus, we hypothesize that mutation of MLL3 will alter the genomic binding and transcriptional regulatory activity of ERα. We investigated the genomic consequences of knocking down MLL3 in an MLL3/PIK3CA WT ER+ breast cancer cell line. Loss of MLL3 led to a large loss of H3K4me1 across the genome, and a shift in genomic location of ERα‐binding sites, which was accompanied by a re‐organization of the breast cancer transcriptome. Gene set enrichment analyses of ERα‐binding sites in MLL3 KD identified endocrine therapy resistance terms, and we showed that MLL3 KD cells are resistant to tamoxifen and fulvestrant. Many differentially expressed genes are controlled by the small collection of new locations of H3K4me1 deposition and ERα binding, suggesting that loss of functional MLL3 leads to new transcriptional regulation of essential genes. Motif analysis of RNA‐seq and ChIP‐seq data highlighted SP1 as a critical transcription factor in the MLL3 KD cells. Differentially expressed genes that display a loss of ERα binding upon MLL3 KD also harbor increased SP1 binding. Our data show that a decrease in functional MLL3 leads to endocrine therapy resistance. This highlights the importance of genotyping patient tumor samples for MLL3 mutation upon initial resection, prior to deciding upon treatment plans. MLL3 is the 6th most commonly mutated gene in ER+ breast cancer patients, however its role in regulating the transcriptional activity of ERα in breast cancer is still unclear. Our data imply that mutations in MLL3 lend to endocrine therapy resistance through an altered genomic enhancer and ERα binding landscape resulting in an altered transcriptome, and therefore genotyping should be done prior to deciding upon course of treatment.
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影响因子：
16.6
作者：
Gellert P;Segal CV;Gao Q;López-Knowles E;Martin LA;Dodson A;Li T;Miller CA;Lu C;Mardis ER;Gillman A;Morden J;Graf M;Sidhu K;Evans A;Shere M;Holcombe C;McIntosh SA;Bundred N;Skene A;Maxwell W;Robertson J;Bliss JM;Smith I;Dowsett M;POETIC Trial Management Group and Trialists
通讯作者：
POETIC Trial Management Group and Trialists
影响因子：
168.9
作者：
Davies, Christina;Pan, Hongchao;Godwin, Jon;Gray, Richard;Arriagada, Rodrigo;Raina, Vinod;Abraham, Mirta;Medeiros Alencar, Victor Hugo;Badran, Atef;Bonfill, Xavier;Bradbury, Joan;Clarke, Michael;Collins, Rory;Davis, Susan R.;Delmestri, Antonella;Forbes, John F.;Haddad, Peiman;Hou, Ming-Feng;Inbar, Moshe;Khaled, Hussein;Kielanowska, Joanna;Kwan, Wing-Hong;Mathew, Beela S.;Mittra, Indraneel;Mueller, Bettina;Nicolucci, Antonio;Peralta, Octavio;Pernas, Fany;Petruzelka, Lubos;Pienkowski, Tadeusz;Radhika, Ramachandran;Rajan, Balakrishnan;Rubach, Maryna T.;Tort, Sera;Urrutia, Gerard;Valentini, Miriam;Wang, Yaochen;Peto, Richard
通讯作者：
Peto, Richard
影响因子：
6.2
作者：
Gong, Yun;Han, Eric Yulong;Sneige, Nour
通讯作者：
Sneige, Nour
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
12.3
作者：
Gonzalez-Perez A;Jene-Sanz A;Lopez-Bigas N
通讯作者：
Lopez-Bigas N