Overcoming Resistance to Endocrine Therapy in Breast Cancer: New Approaches to a Nagging Problem.
Overcoming Resistance to Endocrine Therapy in Breast Cancer: New Approaches to a Nagging Problem.
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DOI：
10.1159/000444451
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Alam-Eldin N
中科院分区：
文献类型：
--
作者：
Luqmani YA;Alam-Eldin N
在大多数女性中，乳腺癌通过过度表达雌激素受体（ER）引起的转录活性增加而进展。治疗策略包括：（i）用芳香酶抑制剂减少循环卵巢雌激素或外周产生的雌激素（在绝经后妇女中）和（ii）应用选择性ER调节剂阻断受体。这些干预措施的成功受到可变但持续的获得性耐药性发作和内在的抗肿瘤活性的限制，尽管约50%的晚期转移性疾病患者具有足够的ER水平，但内在的抗肿瘤活性仍然表现出来。功能性ER的丧失会导致内分泌不敏感、细胞粘附和极性丧失，以及由于上皮癌细胞转分化为间充质样表型（上皮-间充质转化; EMT）而增加的迁移潜力。已经提出了导致治疗失败的多种机制：（i）ER表达的丧失或修饰，包括表观遗传机制，（ii）选择性ER调节剂的激动作用，其可通过增加共激活剂的表达而增强，（iii）通过P450细胞色素的遗传变体的表达减弱他莫昔芬代谢，这导致或多或少的活性代谢物，和（iv）生长因子信号传导增加，特别是通过表皮生长因子受体激活涉及角质形成细胞生长因子、血小板衍生生长因子和核因子κB的途径。此外，最近被认为是关键基因调控因子的小的非编码microRNA在他莫昔芬敏感细胞系与耐药细胞系中表现出差异表达。几项研究表明，使用这些作为目标或作为治疗剂来调节EMT调节剂作为通过逆转EMT逆转侵袭性转移表型的手段的潜力，具有对抗雌激素再致敏的额外益处。
In the majority of women, breast cancer progresses through increased transcriptional activity due to over-expressed oestrogen receptors (ER). Therapeutic strategies include: (i) reduction of circulating ovarian oestrogens or of peripherally produced oestrogen (in postmenopausal women) with aromatase inhibitors and (ii) application of selective ER modulators for receptor blockade. The success of these interventions is limited by the variable but persistent onset of acquired resistance and by an intrinsic refractiveness which manifests despite adequate levels of ER in about 50% of patients with advanced metastatic disease. Loss of functional ER leads to endocrine insensitivity, loss of cellular adhesion and polarity, and increased migratory potential due to trans-differentiation of the epithelial cancer cells into a mesenchymal-like phenotype (epithelial-mesenchymal transition; EMT). Multiple mechanisms contributing to therapeutic failure have been proposed: (i) loss or modification of ER expression including epigenetic mechanisms, (ii) agonistic actions of selective ER modulators that may be enhanced through an increased expression of co-activators, (iii) attenuation of the tamoxifen metabolism through expression of genetic variants of P450 cytochromes which leads to more or less active metabolites and (iv) increased growth factor signalling particularly through epidermal growth factor receptor activation of pathways involving keratinocyte growth factor, platelet-derived growth factor, and nuclear factor κB. In addition, the small non-coding microRNAs, recently recognized as critical gene regulators, exhibit differential expression in tamoxifen-sensitive versus resistant cell lines. Several studies suggest the potential of using these either as targets or as therapeutic agents to modulate EMT regulators as a means of reversing the aggressive metastatic phenotype by reversal of the EMT, with the added benefit of re-sensitization to anti-oestrogens.
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影响因子：
3.7
作者：
Bandyopadhyay A;Wang L;Agyin J;Tang Y;Lin S;Yeh IT;De K;Sun LZ
通讯作者：
Sun LZ
DOI：
10.1126/stke.2003.167.re2
发表时间：
2003-01-28
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Bode, Ann M;Dong, Zigang
通讯作者：
Dong, Zigang
雌激素受体沉默可诱导人乳腺癌细胞上皮细胞向间质细胞的转变。
影响因子：
3.7
作者：
Al Saleh S;Al Mulla F;Luqmani YA
通讯作者：
Luqmani YA
影响因子：
2.5
作者：
Eceles, SA
通讯作者：
Eceles, SA
影响因子：
11.2
作者：
Buffa, Francesca M.;Camps, Carme;Ragoussis, Jiannis
通讯作者：
Ragoussis, Jiannis