Translational Regulation of the Inflammatory Breast Cancer Stem Cell

描述（由申请人提供）：本提案的总体目标是阐明翻译起始复合物eIF4F活性改变的作用，以及eIF4F复合物个体成员在晚期乳腺癌，高级别，晚期炎症性乳腺癌（IBC）最致命的表现之一中对癌症干细胞（CSC或肿瘤起始细胞）的选择性翻译，存活，增殖和无线电抗性的抑制作用。我们计划通过沉默和靶向治疗eIF4F复合物的单个组分及其调节因子的组合来实现这一目标，随后照射和检查CSCs群体的变化以及翻译特征的相关变化，这些变化是通过微阵列分析处理和未处理的CSCs中与多聚体相关的主动翻译mrna来确定的。针对eIF4F成分的几种不同开发阶段的药物的可用性，加上它们通过shRNA沉默的直接下调，将为我们提供一种快速的方法来测试IBC CSCs对放疗敏感的可能性，预计这些抑制剂将进入临床。

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to elucidate the role of altered activity of translation initiation complex eIF4F, and the efficacy of inhibition of individual members of the eIF4F complex in the selective translation, survival, proliferation, and radio- resistance by the cancer stem cell (CSC, or tumor-initiating cell) in one of the most deadly presentations of advanced breast cancer, high grade, advanced stage inflammatory breast cancer (IBC). We plan to achieve this goal by a combination of silencing and targeted treatment of individual components of the eIF4F complex, as well as of their regulators, followed by irradiation and examination in the changes in the population of CSCs as well as the associated changes in translation signatures as determined by microarray analysis of the polysome-associated, actively translating mRNAs in the treated and untreated CSCs. The availability of several drugs in different stages of development targeting eIF4F components, coupled with their direct downregulation by shRNA silencing, will provide us with a rapid way to test the possibility to sensitize IBC CSCs to radiotherapy in anticipation for these inhibitors entering the clinic.