Translational Regulation of the Inflammatory Breast Cancer Stem Cell

描述（申请人提供）：本提案的总体目标是阐明翻译起始复合物eIF 4F活性改变的作用，以及抑制eIF 4F复合物单个成员在癌症干细胞选择性翻译、存活、增殖和放射抗性中的功效。在晚期乳腺癌的最致命的表现之一，高级别，晚期炎症性乳腺癌（IBC）中，CSC或肿瘤起始细胞（tumor-initiating cell）。我们计划通过沉默和靶向治疗eIF 4F复合物的单个组分及其调节剂的组合来实现这一目标，然后照射和检查CSC群体的变化以及翻译特征的相关变化，如通过微阵列分析处理和未处理的CSC中的多核糖体相关的主动翻译mRNA所确定的。针对eIF 4F组分的不同开发阶段的多种药物的可用性，加上它们通过shRNA沉默而直接下调，将为我们提供一种快速的方法来测试IBC CSC对放射治疗敏感的可能性，以期这些抑制剂进入临床。 公共卫生相关性：该研究旨在通过下调特定因子或使用特定药物来研究靶向蛋白质合成机制的效果，以提高放射治疗消除癌症干细胞群的疗效。（CSC，或肿瘤起始细胞），涉及复发和转移，是晚期乳腺癌最致命的表现之一，高级别，晚期炎症性乳腺癌（IBC）。

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).