Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
Breast Cancer Res Treat. 2012 Apr;132(2):537-44. doi: 10.1007/s10549-011-1622-z. Epub 2011 Jun 14.
Interactions between kinases and the estrogen receptor α (ERα) are thought to be a critical signaling pathway in the majority of human breast cancers. We have recently identified a previously uncharacterized molecule, lemur tyrosine kinase-3 (LMTK3) as a prognostic and predictive oncogenic ERα regulator with a central role in endocrine resistance. Unusually this protein has undergone Darwinian positive selection between Chimpanzees and humans suggesting it may contribute to human susceptibility to ERα-positive tumors. Using over 600 European primary breast cancer cases, we wished to establish tumor characteristics associated with both cytoplasmic and nuclear LMTK3 expression, and then externally validate our observed European clinical outcomes with samples from Asian individuals receiving chemotherapy. Both nuclear and cytoplasmic expression correlated with tumor grade (P < 0.001) and in the Asian cohort, independent blinded analyses demonstrated that high basal LMTK3 expression was associated with advanced stage of primary breast cancers as well as decreased overall (P = 0.03) and disease-free survival (P = 0.006). In summary, higher LMTK3 expression is associated with more aggressive cancers. These data support our previous findings and suggest LMTK3 expression may be a reliable new biomarker in breast cancer.
激酶与雌激素受体 α（ERα）之间的相互作用被认为是大多数人类乳腺癌的关键信号通路。我们最近发现了一种以前未被描述的分子，狐猴酪氨酸激酶-3（LMTK3），它是一种预后和预测性的致癌 ERα 调节剂，在内分泌抵抗中起着核心作用。不同寻常的是，这种蛋白质在黑猩猩和人类之间经历了达尔文正选择，这表明它可能有助于人类对 ERα 阳性肿瘤的易感性。我们使用了超过 600 例欧洲原发性乳腺癌病例，希望确定与 LMTK3 核质表达相关的肿瘤特征，然后用接受化疗的亚洲个体的样本对我们观察到的欧洲临床结果进行外部验证。核质表达均与肿瘤分级相关（P < 0.001），在亚洲队列中，独立的盲法分析表明，LMTK3 的基础高表达与原发性乳腺癌的晚期以及总生存期（P = 0.03）和无病生存期（P = 0.006）的降低相关。总之，更高的 LMTK3 表达与更具侵袭性的癌症相关。这些数据支持我们之前的发现，并表明 LMTK3 表达可能是乳腺癌的一种可靠的新生物标志物。
