Farahmand Leila, Mansouri Sepideh, Jafarbeik-Iravani Narges, Teymourzadeh Azin, Majidzadeh-A Keivan
Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Recent Pat Anticancer Drug Discov. 2018;13(3):302-307. doi: 10.2174/1574892813666180305164634.
Tamoxifen is widely administered for patients with estrogen receptor-positive breast cancer. Despite many patients benefiting from Tamoxifen as an effective anti-hormonal agent in adjuvant therapy, a noticeable number of patients tend to develop resistance.
The aim of this study was to shed light upon the molecular mechanisms associated with Tamoxifen resistance which can help improve current treatment strategies available for stimulating responsiveness and combating resistance.
Relevant articles were obtained from PubMed and google scholar, nearly all dated from 2010 to 2017. Articles were screened to select the ones meeting the objective. The molecular interactions in the resistant network were extracted from the appropriate articles.
The mechanisms of developing Tamoxifen resistance were briefly outlined. Overactivation of Receptor Tyrosine Kinases (RTKs) pathways, commonly known as alternative growth cascades, is one of the main players in acquired cancer cell stemness, which can induce unrestricted proliferation in the presence of Tamoxifen. There are seven recent patents including 6291496B1 as an anti-HER2, 8143226B2 as an inhibitor of RTK phosphorylation, 9062308B2 as an anti-HOXB7, Lapatinib functioning as an anti-EGFR/HER2, Everolimus as an inhibitor of mTOR, Exemestane as an aromatase inhibitor and Perifosine as an AKT inhibitor.
Altogether, it seems that tumor cells express a stemness phenotype which tends to override anti-hormonal adjuvant therapies. Since RTKs are overactivated and overexpressed in such cells, specialized targeted therapies suppressing RTKs would be a novel and effective way in restoring Tamoxifen sensitivity in resistant breast cancer tumor cells.
他莫昔芬广泛应用于雌激素受体阳性乳腺癌患者。尽管许多患者在辅助治疗中受益于他莫昔芬这种有效的抗激素药物，但仍有相当数量的患者会产生耐药性。
本研究旨在阐明与他莫昔芬耐药相关的分子机制，这有助于改进目前可用的治疗策略，以提高反应性并对抗耐药性。
从PubMed和谷歌学术搜索中获取相关文章，几乎所有文章的日期都在2010年至2017年之间。对文章进行筛选，以选择符合研究目的的文章。从合适的文章中提取耐药网络中的分子相互作用。
简要概述了他莫昔芬耐药的发生机制。受体酪氨酸激酶（RTK）通路的过度激活，通常被称为替代生长级联反应，是获得性癌细胞干性的主要因素之一，它可在存在他莫昔芬的情况下诱导不受限制的增殖。近期有七项专利，包括作为抗HER2的6291496B1、作为RTK磷酸化抑制剂的8143226B2、作为抗HOXB7的9062308B2、作为抗EGFR/HER2的拉帕替尼、作为mTOR抑制剂的依维莫司、作为芳香化酶抑制剂的依西美坦以及作为AKT抑制剂的哌立福辛。
总体而言，肿瘤细胞似乎表现出一种干性表型，这种表型往往会凌驾于抗激素辅助治疗之上。由于RTK在这类细胞中过度激活和过度表达，抑制RTK的专门靶向治疗将是恢复耐药乳腺癌肿瘤细胞对他莫昔芬敏感性的一种新颖且有效的方法。
