Department of Biomedical Sciences, Gen*NY*Sis Center for Excellence in Cancer Genomics, University at Albany, Rensselaer, NY.
Genes Chromosomes Cancer. 2013 Oct;52(10):961-75. doi: 10.1002/gcc.22091. Epub 2013 Aug 3.
Tyrosine kinases orchestrate key cellular signaling pathways and their dysregulation is often associated with cellular transformation. Several recent cases in which inhibitors of tyrosine kinases have been successfully used as anticancer agents have underscored the importance of this class of proteins in the development of targeted cancer therapies. We have carried out a large-scale loss-of-function analysis of the human tyrosine kinases using RNA interference to identify novel survival factors for breast cancer cells. In addition to kinases with known roles in breast and other cancers, we identified several kinases that were previously unknown to be required for breast cancer cell survival. The most surprising of these was the cytosolic, nonreceptor tyrosine kinase, Bruton's tyrosine kinase (BTK), which has been extensively studied in B cell development. Down regulation of this protein with RNAi or inhibition with pharmacological inhibitors causes apoptosis; overexpression inhibits apoptosis induced by Doxorubicin in breast cancer cells. Our results surprisingly show that BTK is expressed in several breast cancer cell lines and tumors. The predominant form of BTK found in tumor cells is transcribed from an alternative promoter and results in a protein with an amino-terminal extension. This alternate form of BTK is expressed at significantly higher levels in tumorigenic breast cells than in normal breast cells. Since this protein is a survival factor for these cells, it represents both a potential marker and novel therapeutic target for breast cancer.
酪氨酸激酶协调关键的细胞信号通路，其失调通常与细胞转化有关。最近有几个案例表明，酪氨酸激酶抑制剂已被成功用作抗癌药物，这突显了这类蛋白质在开发靶向癌症疗法中的重要性。我们使用 RNA 干扰对人类酪氨酸激酶进行了大规模的功能丧失分析，以鉴定乳腺癌细胞的新生存因子。除了已知在乳腺癌和其他癌症中发挥作用的激酶外，我们还鉴定出了几种以前未知的对乳腺癌细胞生存必需的激酶。其中最令人惊讶的是胞质非受体酪氨酸激酶布鲁顿酪氨酸激酶（BTK），它在 B 细胞发育中已被广泛研究。用 RNAi 下调这种蛋白质或用药理学抑制剂抑制它会导致细胞凋亡；过表达它会抑制乳腺癌细胞中阿霉素诱导的细胞凋亡。我们的结果出人意料地表明，BTK 在几种乳腺癌细胞系和肿瘤中表达。在肿瘤细胞中发现的 BTK 的主要形式是从替代启动子转录而来的，导致蛋白质的氨基末端延伸。这种 BTK 的替代形式在致瘤性乳腺癌细胞中的表达水平明显高于正常乳腺细胞。由于这种蛋白质是这些细胞的生存因子，因此它既是一种潜在的标志物，也是乳腺癌的一个新的治疗靶点。
