Translational Regulation of the Inflammatory Breast Cancer Stem Cell

描述(申请人提供)：这项建议的首要目标是阐明翻译起始复合体eIF4F活性改变的作用，以及eIF4F复合体单个成员在癌症干细胞(CSC，或肿瘤启动细胞)选择性翻译、存活、增殖和放射抵抗中的有效性。我们计划通过沉默和靶向处理eIF4F复合体及其调节因子的单个组件来实现这一目标，然后照射和检查CSCs数量的变化以及通过对处理和未处理的CSCs中的多聚体相关、积极翻译的mRNAs进行微阵列分析所确定的翻译特征的相关变化。针对eIF4F组分的几种药物在不同开发阶段的可用性，加上shRNA沉默对它们的直接下调，将为我们提供一种快速测试在这些抑制剂进入临床之前使IBCSCs对放射治疗敏感的可能性的方法。 公共卫生相关性：拟议的研究旨在调查靶向蛋白质合成机制的效果，通过下调特定因素或使用特定药物，以提高放射治疗在消除癌症干细胞群(CSC或肿瘤启动细胞)方面的疗效，CSC或肿瘤启动细胞与复发和转移有关，在晚期乳腺癌、高级别、晚期炎症性乳腺癌(IBC)中是最致命的表现之一。

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. PUBLIC HEALTH RELEVANCE: The proposed study is aimed at investigating the effect of targeting the protein synthesis machinery, by both downregulation of specific factors or the use of specific drugs, in order to increase the efficacy of radiotherapy in the eliminating the cancer stem cell population (CSC, or tumor-initiating cell), implicated in both recurrence and metastasis, in one of the most deadly presentations of advanced breast cancer, high grade, advanced stage inflammatory breast cancer (IBC).