ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer.,Journal of Cellular Biochemistry

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ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer.
Journal of Cellular Biochemistry ( IF 3.0 ) Pub Date : 2020-07-06 , DOI: 10.1002/jcb.29762
Guoqiang Hua _{1,

2,

3} , Aurélie Bergon ₁ , Pierre Cauchy _{1,

4} , Brigitte Kahn-Perlès ₁ , François Bertucci ₅ , Daniel Birnbaum ₅ , Nadia Benkirane-Jessel _{2,

3} , Jean Imbert ₁

Affiliation

The presence of nuclear ERBB2 receptor‐type tyrosine kinase is one of the causes of the resistance to membrane ERBB2‐targeted therapy in breast cancers. It has been previously reported that this nuclear location arises through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full‐length receptor and translation of the messenger RNA (mRNA)‐encoding ERBB2 from internal initiation codons. Here, we report a new mechanism and function where a significant portion of nuclear ERBB2 results from the translation of the variant ERBB2 mRNA under the transcriptional control of a distal promoter that is actively used in breast cancer cells. We show that both membrane ERBB2a and nuclear ERBB2b isoforms are prevalently expressed in breast cancer cell lines and carcinoma samples. The ERBB2b isoform, which is translated from mRNA variant 2, can directly translocate into the nucleus due to the lack of the signal peptide which is required for an intermediate membrane location. Small interfering RNA‐mediated gene silencing showed that ERBB2b can repress ERBB2a expression, encoded by variant 1, whereas ERBB2a activates ERBB2b. Nuclear ERBB2 binding to its own promoter was revealed by chromatin immunoprecipitation assay. Altogether, our results provide new insights into the origin and function of nuclear ERBB2 where it can participate at the same time in a positive or a negative feedback autoregulatory loop, dependent on which of its promoters this bona fide transcription factor is acting. They also provide a new understanding for the resistance to therapies targeting the membrane‐anchored ERBB2 in breast cancer.

中文翻译：

ERBB2b mRNA 亚型编码乳腺癌中 ERBB2 癌基因的核变体。

核ERBB2受体型酪氨酸激酶的存在是乳腺癌膜ERBB2靶向治疗耐药的原因之一。此前已有报道称，这种核位置至少通过两种不同的机制产生：全长受体胞外结构域的蛋白水解脱落和编码 ERBB2 的信使 RNA (mRNA)从内部起始密码子的翻译。在这里，我们报告了一种新的机制和功能，其中核 ERBB2 的很大一部分是由变体ERBB2 mRNA 在乳腺癌细胞中活跃使用的远端启动子的转录控制下翻译产生的。我们发现膜 ERBB2a 和核 ERBB2b 亚型在乳腺癌细胞系和癌症样本中普遍表达。ERBB2b 同工型由 mRNA 变体 2 翻译而来，由于缺乏中间膜位置所需的信号肽，可以直接转位到细胞核中。小干扰RNA介导的基因沉默表明，ERBB2b可以抑制由变体1编码的ERBB2a表达，而ERBB2a则激活ERBB2b。通过染色质免疫沉淀测定揭示了细胞核 ERBB2 与其自身启动子的结合。总而言之，我们的结果为核 ERBB2 的起源和功能提供了新的见解，它可以同时参与正反馈或负反馈自动调节环，具体取决于该真正转录因子正在发挥作用的启动子。他们还为乳腺癌中针对膜锚定 ERBB2 的疗法的耐药性提供了新的认识。

更新日期：2020-07-06

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