The Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, IL, USA.
Onco Targets Ther. 2013 Jul 23;6:943-55. doi: 10.2147/OTT.S33766. Print 2013.
The numerous processes involved in the etiology of breast cancer such as cell survival, metabolism, proliferation, differentiation, and angiogenesis are currently being elucidated. However, underlying mechanisms that drive breast cancer progression and drug resistance are still poorly understood. As we discuss here in detail, the Notch signaling pathway is an important regulatory component of normal breast development, cell fate of normal breast stem cells, and proliferation and survival of breast cancer initiating cells. Notch exerts a wide range of critical effects through a canonical pathway where it is expressed as a type I membrane precursor heterodimer followed by at least two subsequent cleavages induced by ligand engagement to ultimately release an intracellular form to function as a transcriptional activator. Notch and its ligands are overexpressed in breast cancer, and one method of effectively blocking Notch activity is preventing its cleavage at the cell surface with γ-secretase inhibitors. In the context of Notch signaling, the application of clinically relevant anti-Notch drugs in treatment regimens may contribute to novel therapeutic interventions and promote more effective clinical response in women with breast cancer.
乳腺癌的发生涉及许多过程，如细胞存活、代谢、增殖、分化和血管生成等，目前正在阐明。然而，驱动乳腺癌进展和耐药性的潜在机制仍知之甚少。正如我们在这里详细讨论的那样，Notch 信号通路是正常乳腺发育、正常乳腺干细胞的细胞命运以及乳腺癌起始细胞增殖和存活的重要调节组成部分。Notch 通过一个经典途径发挥广泛的关键作用，在该途径中，它作为一种 I 型膜前体异二聚体表达，然后至少通过两次后续切割，由配体结合诱导，最终释放一种细胞内形式作为转录激活剂发挥作用。Notch 和其配体在乳腺癌中过度表达，有效阻断 Notch 活性的一种方法是用γ-分泌酶抑制剂阻止其在细胞表面的切割。在 Notch 信号通路的背景下，在治疗方案中应用临床相关的抗 Notch 药物可能有助于新的治疗干预，并促进乳腺癌女性更有效的临床反应。
