Notch Signaling in Breast Cancer: A Role in Drug Resistance.
Notch Signaling in Breast Cancer: A Role in Drug Resistance.
复制标题
Notch信号在乳腺癌耐药中的作用。
作者：
BeLow M;Osipo C
乳腺癌是一种异质性疾病，根据雌激素受体、孕激素受体和/或人表皮生长因子受体2的蛋白表达情况，可将其细分为独特的分子亚型。治疗方法旨在通过内分泌治疗、靶向治疗或与细胞毒性化疗相结合来抑制这些过度表达的受体。然而，相当大比例的乳腺癌对治疗具有先天或获得性耐药性，促进耐药性的机制仍然知之甚少。Notch信号是一种进化上保守的信号通路，它调节细胞的命运，包括干细胞的存活和自我更新、增殖或分化。解除对Notch信号的调控，通过丰富实体肿瘤内一小部分耐药细胞(称为乳腺癌干细胞)，增强肿瘤细胞去分化过程中的干细胞样特征，或促进上皮细胞向间充质细胞的转变，来促进对靶向或细胞毒性治疗的耐药性。临床前研究表明，靶向Notch通路可以通过减少或消除乳腺癌干细胞来防止或逆转耐药性。然而，Notch抑制剂尚未被临床批准用于乳腺癌的治疗，主要是由于剂量限制的胃肠道毒性。在这篇综述中，我们讨论了Notch介导的乳腺癌细胞和乳腺癌干细胞耐药的潜在机制，以及通过γ分泌酶抑制剂、Notch信号生物制品或转录抑制剂靶向Notch的各种方法。我们还讨论了未来确定新的Notch靶向治疗方法的计划，以减少毒性并改善耐药乳腺癌患者的预后。
Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate, including survival and self-renewal of stem cells, proliferation, or differentiation. Deregulation of Notch signaling promotes resistance to targeted or cytotoxic therapies by enriching of a small population of resistant cells, referred to as breast cancer stem cells, within the bulk tumor; enhancing stem-like features during the process of de-differentiation of tumor cells; or promoting epithelial to mesenchymal transition. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance through reduction or elimination of breast cancer stem cells. However, Notch inhibitors have yet to be clinically approved for the treatment of breast cancer, mainly due to dose-limiting gastrointestinal toxicity. In this review, we discuss potential mechanisms of Notch-mediated resistance in breast cancer cells and breast cancer stem cells, and various methods of targeting Notch through γ-secretase inhibitors, Notch signaling biologics, or transcriptional inhibitors. We also discuss future plans for identification of novel Notch-targeted therapies, in order to reduce toxicity and improve outcomes for women with resistant breast cancer.
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影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
3.8
作者：
Cohen, Brenda;Shimizu, Mamiko;Reedijk, Michael
通讯作者：
Reedijk, Michael
影响因子：
3.9
作者：
Abdel-Rahman, Noha;Martinez-Arias, Alfonso;Blundell, Tom L.
通讯作者：
Blundell, Tom L.
DOI：
10.1073/pnas.0603806103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Chute, John P.;Muramoto, Garrett G.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
11.4
作者：
Cheung, A. M. S.;Wan, T. S. K.;Leung, A. Y. H.
通讯作者：
Leung, A. Y. H.