Darvishi Behrad, Farahmand Leila, Eslami-S Zahra, Majidzadeh-A Keivan
1 Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
2 Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, 1517964311 Tehran, Iran.
Tumour Biol. 2017 Jun;39(6):1010428317706919. doi: 10.1177/1010428317706919.
Graphical abstract Although accounting for merely a minute portion of diagnosed breast cancers, disproportionate number of deaths and associated low survival rate of patients have made triple-negative breast cancer to be considered as the most lethal breast cancer subtype. More importantly, intrinsic or developed resistance to chemotherapeutic regimens and disappointing outcomes of trials associated with many newly developed agents are other obstacles in establishment of a durable response in these patients. Interestingly, these happen despite the outstanding preclinical outcomes observed by these agents, most importantly among them, targeted receptor tyrosine kinase inhibitors. Pursuing these disappointing outcomes, especially in the case of targeted receptor tyrosine kinase inhibitors, many researches have focused on identification of the hidden factors involved. Highly inflammatory, rich in reactive oxygen species, and hypoxic microenvironment of triple-negative breast cancer tumors and the involving mediators were the first suggestions for observed resistance and poor clinical outcomes of targeted receptor tyrosine kinase inhibitors. Interestingly, for all aberrantly expressed mediators observed in microenvironment, downstream pathways converge in a common node, nothing but the nuclear factor-κB, the insidious factor proposed to be the cause of many events opposing achievement of a desired outcome. In first section of current review, we describe the signaling pathways underlying activation of receptor tyrosine kinases and their convergence at the nuclear factor-κB node, and in next section, we demonstrate how unique hypoxic, inflammatory, rich in free-radical microenvironment of triple-negative breast cancer exacerbate pathways in which otherwise could become mostly suppressed by receptor tyrosine kinase inhibitors.
图形摘要 尽管三阴性乳腺癌在已诊断的乳腺癌中仅占极小部分，但死亡人数不成比例且患者生存率较低，这使得三阴性乳腺癌被认为是最致命的乳腺癌亚型。更重要的是，对化疗方案的内在或获得性耐药以及与许多新开发药物相关的试验结果令人失望，是在这些患者中建立持久反应的其他障碍。有趣的是，尽管这些药物在临床前观察到了出色的结果，其中最重要的是靶向受体酪氨酸激酶抑制剂，但仍出现了上述情况。鉴于这些令人失望的结果，尤其是在靶向受体酪氨酸激酶抑制剂的情况下，许多研究都集中在识别其中涉及的隐藏因素上。三阴性乳腺癌肿瘤高度炎症、富含活性氧且缺氧的微环境以及其中涉及的介质，是靶向受体酪氨酸激酶抑制剂出现耐药和临床结果不佳的最初推测原因。有趣的是，对于在微环境中观察到的所有异常表达的介质，其下游途径都汇聚于一个共同节点，即核因子-κB，这个潜在因素被认为是许多阻碍实现预期结果的事件的原因。在本综述的第一部分，我们描述了受体酪氨酸激酶激活的信号通路及其在核因子-κB节点的汇聚，在下一部分，我们将展示三阴性乳腺癌独特的缺氧、炎症、富含自由基的微环境如何加剧那些原本可能被受体酪氨酸激酶抑制剂大多抑制的途径。
