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Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets.
Oncogene ( IF 6.9 ) Pub Date : 2018-Aug-01 , DOI: 10.1038/s41388-018-0284-2
Leah A Gates 1, 2 , Guowei Gu 1, 3 , Yue Chen 4 , Aarti D Rohira 1 , Jonathan T Lei 3, 5 , Ross A Hamilton 1 , Yang Yu 1 , David M Lonard 1 , Jin Wang 1, 6, 7 , Shu-Ping Wang 8 , David G Edwards 3 , Philip F Lavere 1 , Jiangyong Shao 1 , Ping Yi 1 , Antrix Jain 1 , Sung Yun Jung 9 , Anna Malovannaya 1, 9 , Shunqiang Li 10 , Jieya Shao 10 , Robert G Roeder 8 , Matthew J Ellis 3, 5, 11 , Jun Qin 1, 9 , Suzanne A W Fuqua 3, 11 , Bert W O'Malley 1, 11 , Charles E Foulds 1, 12
Affiliation  

Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.

中文翻译:

蛋白质组学分析确定了突变 ERα 蛋白利用的关键共激活因子作为潜在的新治疗靶点。

大约 75% 的乳腺癌是雌激素受体 α (ERα) 阳性,可以通过内分泌疗法进行治疗,但患者通常会发展为致命的耐药性疾病。已鉴定出编码 ERα (ESR1) 的基因中配体结合域 (LBD) 密码子中的频繁突变 (10-40%),从而产生不依赖配体的组成型活性受体。此外,可能会发生 ESR1 染色体易位,导致融合蛋白缺乏 LBD 并且对所有内分泌治疗完全无反应。因此,鉴定与这些突变 ERα 蛋白结合的共激活剂可能为内分泌抗性癌症提供新的治疗靶点。为了定义共激活剂候选目标,我们采用蛋白质组学方法分析招募到两种最常见的 ERα LBD 突变体 Y537S 和 D538G 以及 ESR1-YAP1 融合蛋白的蛋白质。与未配体的野生型 ERα 相比,这些突变体显示出增强的共激活剂相互作用。这些共激活因子的抑制降低了 ESR1 突变体在体外和体内激活转录和促进乳腺癌生长的能力。因此,我们已经确定了可用作内分泌抗性乳腺癌靶标的特定共激活剂。
更新日期:2018-05-11
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