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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Brk is coamplified with ErbB2 to promote proliferation in breast cancer
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Brk is coamplified with ErbB2 to promote proliferation in breast cancer

机译：Brk与ErbB2共同扩增以促进乳腺癌的增殖

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摘要

Amplification of the receptor tyrosine kinase ErbB2 is frequently observed in breast cancer. Amplification of erbB2 is also associated with multiple genomic gains and losses; however, the importance of these associated changes is largely unknown. We demonstrate that Brk, a cytoplasmic tyrosine kinase, is coamplified and coexpressed with ErbB2 in human breast cancers. ErbB2 interacts with Brk and increases its intrinsic kinase activity. Expression of Brk enhances the ErbB2-induced activation of Ras/MAPK signaling and cyclin E/cdk2 activity to induce cell proliferation of mammary 3-dimensional acini in culture. In a murine model of breast cancer, expression of Brk was found to shorten the latency of ErbB2-induced tumors by promoting cell proliferation, with no effect on protection from apoptosis. Furthermore, overexpression of Brk conferred resistance to the ability of Lapatinib, an ErbB2 kinase inhibitor, to inhibit ErbB2-induced proliferation. Thus, we identified Brk as a drug target for ErbB2-positive cancers.
机译：在乳腺癌中经常观察到受体酪氨酸激酶ErbB2的扩增。 erbB2的扩增还与多种基因组的得失有关。但是，这些相关更改的重要性很大程度上未知。我们证明，Brk，一种细胞质酪氨酸激酶，在人类乳腺癌中被共扩增并与ErbB2共表达。 ErbB2与Brk相互作用并增加其固有的激酶活性。 Brk的表达增强了ErbB2诱导的Ras / MAPK信号转导的激活和细胞周期蛋白E / cdk2的活性，从而诱导培养物中的乳腺3维腺泡的细胞增殖。在乳腺癌的小鼠模型中，发现Brk的表达通过促进细胞增殖来缩短ErbB2诱导的肿瘤的潜伏期，而对细胞凋亡的保护没有影响。此外，Brk的过表达赋予了对Lapatinib（一种ErbB2激酶抑制剂）抑制ErbB2诱导的增殖的能力的抗性。因此，我们确定Brk为ErbB2阳性癌症的药物靶标。

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