Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.
Horm Cancer. 2019 Jun;10(2-3):64-70. doi: 10.1007/s12672-018-0356-3. Epub 2019 Jan 17.
Membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbB family of receptor tyrosine kinases, occurs in 15-20% of breast cancers (BC) and constitutes a therapeutic target in this BC subtype (ErbB-2-positive). Although MErbB-2-targeted therapies have significantly improved patients' clinical outcome, resistance to available drugs is still a major issue in the clinic. Lack of accurate biomarkers for predicting responses to anti-ErbB-2 drugs at the time of diagnosis is also an important unresolved issue. Hence, a better understanding of the ErbB-2 signaling pathway constitutes a critical task in the battle against BC. In its canonical mechanism of action, MErbB-2 activates downstream signaling pathways, which transduce its proliferative effects in BC. The dogma of ErbB-2 mechanism of action has been challenged by the demonstration that MErbB-2 migrates to the nucleus, where it acts as a transcriptional regulator. Accumulating findings demonstrate that nuclear ErbB-2 (NErbB-2) is involved in BC growth and metastasis. Emerging evidence also reveal a role of NErbB-2 in the response to available anti-MErbB-2 agents. Here, we will review NErbB-2 function in BC and will particularly discuss the role of NErbB-2 as a novel target for therapy in ErbB-2-positive BC.
膜过表达 ErbB-2（MErbB-2），受体酪氨酸激酶 ErbB 家族的一员，在 15-20%的乳腺癌（BC）中发生，构成了这种 BC 亚型（ErbB-2 阳性）的治疗靶点。尽管针对 MErbB-2 的靶向治疗显著改善了患者的临床结局，但对现有药物的耐药性仍然是临床中的一个主要问题。在诊断时缺乏准确的生物标志物来预测对抗 ErbB-2 药物的反应也是一个重要的未解决问题。因此，更好地了解 ErbB-2 信号通路是对抗 BC 的关键任务。在其经典的作用机制中，MErbB-2 激活下游信号通路，将其在 BC 中的增殖作用传递下去。MErbB-2 迁移到细胞核并作为转录调节剂发挥作用的发现，对 ErbB-2 作用机制的教条提出了挑战。越来越多的研究结果表明，核 ErbB-2（NErbB-2）参与了 BC 的生长和转移。新出现的证据还揭示了 NErbB-2 在对现有抗 MErbB-2 药物的反应中的作用。在这里，我们将回顾 NErbB-2 在 BC 中的功能，并特别讨论 NErbB-2 作为 ErbB-2 阳性 BC 治疗新靶点的作用。
