Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab
Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab
复制标题
环状 HER2 RNA 阳性三阴性乳腺癌对帕妥珠单抗敏感。
DOI：
10.1186/s12943-020-01259-6
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发表时间：
2020-09-11
期刊：
影响因子：
37.3
通讯作者：
Zhang, Nu
中科院分区：
文献类型：
--
作者：
Li, Jie;Ma, Maoguang;Zhang, Nu
背景：三阴性乳腺癌（TNBC）仍然是迄今为止最具挑战性的乳腺癌亚型。具体的治疗方法很少在TNBC患者的治疗中取得临床改善，有效的分子生物标志物在很大程度上尚不清楚。方法：我们使用配对TNBC样本和高通量RNA测序来鉴定差异表达的circRNA。使用蔗糖梯度多核糖体分级分离测定、抗体和质谱来验证活性circRNA翻译。通过功能获得或丧失测定在体外和体内验证新蛋白质功能。结果：环状HER 2 RNA（circ-HER 2）编码一种新的蛋白质，HER 2 -103。出乎意料的是，虽然几乎没有检测到HER 2 mRNA和蛋白质，但circ-HER 2/HER 2 -103在类似于30% TNBC临床样品中表达。Circ-HER 2/HER 2 -103阳性TNBC患者比circ-HER 2/HER 2 -103阴性患者具有更差的总体预后。敲低circ-HER 2在体外和体内抑制TNBC细胞增殖、侵袭和肿瘤发生，表明circ-HER 2/HER 2 -103在TNBC致瘤性中的关键作用。在机制上，HER 2 -103促进表皮生长因子受体（EGFR）/HER 3的同源/异源二聚化，维持AKT磷酸化和下游恶性表型。此外，HER 2 -103与HER 2 CR 1结构域共享大部分相同的氨基酸序列，这可以被临床使用的HER 2抗体帕妥珠单抗拮抗。帕妥珠单抗显著减弱表达circ-HER 2/HER 2 -103的TNBC细胞的体内致瘤性，但在circ-HER 2/HER 2 -103阴性的TNBC细胞中没有显示效果。结论：我们的结果不仅证明某些TNBC不是真正的“HER 2阴性”，而且还强调了帕妥珠单抗在表达circ-HER 2/HER 2 -103的TNBC患者中的临床意义。
Background: Triple negative breast cancer (TNBC) remains the most challenging breast cancer subtype so far. Specific therapeutic approaches have rarely achieved clinical improvements in treatment of TNBC patients and effective molecular biomarkers are largely unknown.Methods: We used paired TNBC samples and high throughput RNA sequencing to identify differentially expressed circRNAs. Sucrose gradient polysome fractionation assay, antibody and Mass spectra were used to validate active circRNA translation. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses and kinase activity assay.Results: Circular HER2 RNA (circ-HER2) encoded a novel protein, HER2-103. Unexpectedly, while HER2 mRNA and protein were barely detected, circ-HER2/HER2-103 was expressed in similar to 30% TNBC clinical samples. Circ-HER2/HER2-103 positive TNBC patients harbored worse overall prognosis than circ-HER2/HER2-103 negative patients. Knockdown circ-HER2 inhibited TNBC cells proliferation, invasion and tumorigenesis in vitro and in vivo, suggesting the critical role of circ-HER2/HER2-103 in TNBC tumorigenicity. Mechanistically, HER2-103 promoted homo/hetero dimerization of epidermal growth factor receptor (EGFR)/HER3, sustained AKT phosphorylation and downstream malignant phenotypes. Furthermore, HER2-103 shared most of the same amino acid sequences as HER2 CR1 domain which could be antagonized by Pertuzumab, a clinical used HER2 antibody. Pertuzumab markedly attenuated in vivo tumorigenicity of circ-HER2/HER2-103 expressing TNBC cells but showed no effects in circ-HER2/HER2-103 negative TNBC cells.Conclusion: Our results not only demonstrated that certain TNBCs were not truly 'HER2 negative' but also highlighted the clinical implications of Pertuzumab in circ-HER2/HER2-103 expressing TNBC patients.