Complex Role of HSF1 in Breast Cancer

HSF1 在乳腺癌中的复杂作用

基本信息

批准号：
9011509
负责人：
STUART Keith CALDERWOOD
金额：
$ 35.57万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9011509
关键词：
Address Adriamycin PFS Affect Aneuploidy Animal Model Animals Binding Breast Cancer Cell Cell Culture Techniques Cell model Cells Chromosome abnormality Complex Control Animal Data Development Disease Drug resistance EP300 gene ERBB2 gene Epithelial Essential Genes Etiology Gene Dosage Gene Expression Genetic Transcription HSF1 Health Heat shock proteins Heat-Shock Response Homeostasis Hyperthermia Ionizing radiation Knock-out Lesion Link Maintenance Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Mesenchymal Modeling Molecular Molecular Chaperones Molecular Weight Mus Neoplasm Metastasis NuRD complex Oncogenes Pathway interactions Pharmaceutical Preparations Phosphotransferases Play Population Premalignant Protein Biosynthesis Proteins Proxy Publishing Radiation Radiation Tolerance Regulation Research Resistance Role SWI/SNF Family Complex Severity of illness Signal Pathway Signal Transduction Signal Transduction Pathway Stem Cell Factor Stem cells Stress Testing Tissues Tumor Angiogenesis angiogenesis base cancer cell cancer stem cell cancer therapy cancer type chromatin remodeling experience gene repression heat shock transcription factor heat-shock factor 1 inhibitor/antagonist knock-down malignant breast neoplasm mouse model outcome forecast programs protein complex radiation resistance radiation response research study response senescence stemness translational study tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): HSF1 is the key transcriptional regulator of heat shock protein synthesis that defines the response to hyperthermia, and affects resistance to certain conventional drugs and radiation. Recently, based on both model and population studies, Hsf1 has emerged as a major factor in breast cancer development. We have demonstrated that HSF1 plays an essential role in malignant transformation and maintenance of cancer cells by controlling oncogene-induced senescence, and tumor angiogenesis. To advance our understanding of oncogenesis and radiation resistance, and to rationally target Hsf1 in specific cancer types, here we will address fundamental questions: (1) what are the key mechanisms of Hsf1 activation in Her2-positive cancer, (2) how does Hsf1 affect development and progression of Her2-positive breast cancer, and (3) what is the role of HSF1 in resistance to ionizing radiation. Aim 1 will address how HSF1 is regulated in mammary tumorigenesis. We will elucidate whether Hsf1 is constitutively activated in tumors because of aneuploidy-associated proteotoxicity by co-opting the signal transduction pathways observed in the heat shock response, or as a part of conventional HER2- mediated cancer signaling. In Aim 2, we will clarify how Hsf1 enters functional complexes in response to Her2, and affects global transcription. We will then elucidate the role of transcription mediated by HSF1 in the cancer cells, establishing HSF1 as a cancer stem cell factor, a player in epithelial/mesenchymal transition and a determinant of tumor metastasis (Aim 3). Finally, we will establish how Hsf1 determines cancer responses to ionizing radiation by testing a hypothesis that radiation resistance is linked to Hsf1 mediated control of cancer stem cells.

描述（由申请人提供）：HSF1是热休克蛋白合成的关键转录调节因子，它决定了对高热的反应，并影响对某些常规药物和辐射的抵抗力。最近，基于模型和人群研究，Hsf1 已成为乳腺癌发展的主要因素。我们已经证明，HSF1 通过控制癌基因诱导的衰老和肿瘤血管生成，在癌细胞的恶性转化和维持中发挥重要作用。为了加深我们对肿瘤发生和放射抗性的理解，并在特定癌症类型中合理地靶向 Hsf1，在这里我们将解决一些基本问题：（1）Her2 阳性癌症中 Hsf1 激活的关键机制是什么，（2）Hsf1 如何作用于 Her2 阳性癌症？影响 Her2 阳性乳腺癌的发生和进展，以及 (3) HSF1 在抵抗电离辐射中的作用。目标 1 将解决 HSF1 在乳腺肿瘤发生中如何受到调节。我们将通过选择在热休克反应中观察到的信号转导途径或作为传统 HER2 介导的癌症信号传导的一部分来阐明 Hsf1 是否由于非整倍体相关的蛋白毒性而在肿瘤中被组成性激活。在目标 2 中，我们将阐明 Hsf1 如何响应 Her2 进入功能复合物，并影响全局转录。然后，我们将阐明 HSF1 介导的转录在癌细胞中的作用，确立 HSF1 作为癌症干细胞因子、上皮/间质转化的参与者和肿瘤转移的决定因素（目标 3）。最后，我们将通过测试辐射抗性与 Hsf1 相关的假设来确定 Hsf1 如何确定癌症对电离辐射的反应介导的癌症干细胞控制。