Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
Mol Cancer Res. 2020 Sep;18(9):1257-1270. doi: 10.1158/1541-7786.MCR-20-0067. Epub 2020 Jun 5.
Epithelial-mesenchymal transition (EMT) programs play essential functions in normal morphogenesis and organogenesis, including that occurring during mammary gland development and glandular regeneration. Historically, EMT programs were believed to reflect a loss of epithelial gene expression signatures and morphologies that give way to those associated with mesenchymal cells and their enhanced migratory and invasive behaviors. However, accumulating evidence now paints EMT programs as representing a spectrum of phenotypic behaviors that also serve to enhance cell survival, immune tolerance, and perhaps even metastatic dormancy. Equally important, the activation of EMT programs in transformed mammary epithelial cells not only enhances their acquisition of invasive and metastatic behaviors, but also expands their generation of chemoresistant breast cancer stem cells (BCSC). Importantly, the net effect of these events results in the appearance of recurrent metastatic lesions that remain refractory to the armamentarium of chemotherapies and targeted therapeutic agents deployed against advanced stage breast cancers. Here we review the molecular and cellular mechanisms that contribute to the pathophysiology of EMT programs in human breast cancers and how these events impact their "stemness" and acquisition of chemoresistant phenotypes.
上皮-间充质转化（EMT）程序在正常形态发生和器官发生中发挥着重要作用，包括乳腺发育和腺再生过程中的发生。历史上，EMT 程序被认为反映了上皮基因表达特征和形态的丧失，这些特征和形态让位于与间充质细胞相关的特征和形态，并增强了它们的迁移和侵袭行为。然而，现在越来越多的证据表明 EMT 程序代表了一系列表型行为，这些行为也有助于增强细胞存活、免疫耐受，甚至可能有助于转移性休眠。同样重要的是，转化的乳腺上皮细胞中 EMT 程序的激活不仅增强了它们获得侵袭和转移行为的能力，而且还扩大了它们产生化疗耐药性乳腺癌干细胞（BCSC）的能力。重要的是，这些事件的净效应导致出现复发性转移性病变，这些病变仍然对针对晚期乳腺癌的化疗药物和靶向治疗药物的武器库产生抗药性。在这里，我们回顾了导致人类乳腺癌 EMT 程序发生的分子和细胞机制，以及这些事件如何影响它们的“干性”和获得化疗耐药表型。
