Role of Heat Shock Transcription Factor Hsf1 in Tumorigenesis

热休克转录因子Hsf1在肿瘤发生中的作用

• 批准号: 8067145
• 负责人: NAHID F MIVECHI
• 金额: $ 28.2万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067145
• 关键词: Ablation; Accounting; Address; Animal Model; Biochemical; Biological Models; Breast Cancer Model; Cancer Biology; Cancer Model; Cell Survival; Chemicals; Chronic; Clinic; Critical Pathways; Data; Development; Diethylnitrosamine; Environment; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Gene Targeting; Generations; Genes; Growth; Heat shock proteins; Hepatocyte; Her2/erbb2/neu Staining Method; Human; Incidence; Inflammation; Inflammatory Response; Investigation; Knock-in Mouse; Laboratories; Liver; Lymphoma; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mitogen-Activated Protein Kinases; Modality; Modeling; Modification; Molecular; Molecular Chaperones; Mouse Mammary Tumor Virus; Mus; Mutant Strains Mice; Mutation; Names; Pathogenesis; Phosphorylation; Phosphorylation Site; Primary carcinoma of the liver cells; Property; Proteins; Proto-Oncogenes; Regulation; Repression; Resistance; Role; Side; Signal Transduction; Technology; Testing; Trans-Activators; Transgenic Mice; Up-Regulation; Whole Organism; base; cell transformation; cell type; cellular development; comparative; heat shock transcription factor; knockout gene; macrophage; mammary epithelium; mouse model; neoplastic cell; novel therapeutics; overexpression; public health relevance; receptor; response; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): A hallmark in the pathogenesis of cancer is the increased expression of heat shock proteins (Hsps) and other molecular chaperones. This has been observed in many human tumor types, and is considered to be an adaptive response to enhance tumor cell survival. Heat shock transcription factor 1 (Hsf1) is a major transactivator of Hsps and other molecular chaperones. Results from our laboratory and others indicate significant tumor inhibitory effect for specific tumor types in the absence of the hsf1 gene, suggesting it may be an excellent molecule for targeted therapy in the clinic. However, the extent to which hsf1 ablation can negatively impact a broad range of different tumor types need to be established. In addition, the mechanisms underlying the significant inhibition of tumorigenesis in the absence of the hsf1 gene, specifically for those tumor types that are impacted by inflammation, or are of epithelial origin that account for most malignancies remain largely unknown and needs further investigation. Mutant mice deficient in Hsf1 generated in our laboratory by conventional or conditional gene targeting strategies as well as a knock-in mouse line carrying Hsf1 with the S303A/S307A phosphorylation mutation (hsf14P), which predictably leads to a more transcriptionally active form of Hsf1, offer unique opportunities to address these important issues in the cancer biology at the whole organism level. During the next project period we plan to determine the impact of Hsf1 deletion in two tumor model systems: (1) a chemically induced hepatocellular carcinoma (HCC) that is a well-established model for chronic inflammation-induced cancer, and (2) a model of spontaneous mammary tumorigenesis that expresses Her2/Neu directed to the mammary gland epithelium. In Aim 1, we will test the hypothesis that ablation of Hsf1, negatively impact cell transformation and HCC tumor progression largely based on the property to regulate components of inflammatory response in the tumor environment. We will: (1) determine the intrinsic and extrinsic factors involved in diethylnitrosamine-induced HCC when Hsf1 is deleted from the whole organism, or when it is deleted from specific cell types (e.g., hepatocytes or macrophages), and (2) examine HCC development under conditions where Hsf1 is constitutively active due to mutations in phosphorylation sites (hsf14P mice). In Aim 2, we will test the hypothesis that hsf1 deficiency leads to reduction in mammary tumorigenesis induced by overexpression of Her2/Neu and this occurs through modification of the balance between prosurvival signaling induced by overexpression of Her2/Neu and anti- proliferative signaling induced by TGF2. We will (1) determine the role of Hsf1 in development of mammary tumors using transgenic mouse model expressing Her2/Neu proto-oncogene in mammary epithelium crossed with hsf1-deficient mice, and (2) determine the impact of hsf1 deficiency on mammary tumorigenesis when hsf1 is specifically deleted from epithelial cells before, or after, the initiation of tumorigenesis. We will use a conditional gene knockout technology to examine the effects of hsf1 deficiency in the Her2/Neu-induced breast cancer model for tumors of epithelial origin. PUBLIC HEALTH RELEVANCE: Heat shock transcription factor 1 (Hsf1) is a major transactivator of heat shock proteins (Hsps) and other molecular chaperones that are often overexpressed in human tumors leading to development of cellular resistance to various treatment modalities. We have generated mouse models deficient in Hsf1 and have tested their response in two cancer models; (1) A chemically-induced hepatocellular carcinoma (HCC), and (2) a spontaneous mammary tumorigenesis model that expresses Her2/Neu directed to the mammary gland epithelium. We have found that Hsf1 deficient mice exhibit significant reduction in both tumorigenesis models. In proposed studies, we will examine the underlying mechanisms involved in this tumor inhibitory effect when Hsf1 is deleted from tumors using the above mouse models in anticipation of generation of novel therapeutics to inhibit this protein in human tumors.

描述（由申请人提供）：癌症发病机理的标志是热休克蛋白（HSP）和其他分子伴侣的表达增加。在许多人类肿瘤类型中都观察到了这一点，被认为是增强肿瘤细胞存活的适应性反应。热休克转录因子1（HSF1）是HSP和其他分子伴侣的主要反式激活因子。我们实验室和其他实验室的结果表明，在没有HSF1基因的情况下，对特定肿瘤类型的肿瘤抑制作用显着，这表明它可能是诊所靶向治疗的极好分子。但是，需要建立HSF1消融的程度会对广泛的不同肿瘤类型产生负面影响。此外，在没有HSF1基因的情况下，肿瘤发生显着抑制的基础机制，特别是针对受炎症影响的肿瘤类型，或者是上皮起源，这些肿瘤起源是大多数恶性肿瘤仍然很大程度上未知并需要进一步研究。通过常规或条件基因靶向策略以及带有S303A/S307A磷酸化突变（HSF14P）携带HSF1的敲门小鼠在我们的实验室产生的HSF1的突变小鼠，可以预见，这可以预测，这会导致更具转录活性的HSF1，可在这些癌症中占有独特的机构。 During the next project period we plan to determine the impact of Hsf1 deletion in two tumor model systems: (1) a chemically induced hepatocellular carcinoma (HCC) that is a well-established model for chronic inflammation-induced cancer, and (2) a model of spontaneous mammary tumorigenesis that expresses Her2/Neu directed to the mammary gland epithelium.在AIM 1中，我们将检验以下假设：HSF1的消融，细胞转化和HCC肿瘤进展很大程度上基于特性，以调节肿瘤环境中炎症反应的成分。我们将：（1）确定当HSF1从整个生物体中删除时，或从特定细胞类型中删除HSF1时，与二乙基硝基胺诱导的HCC相关的固有和外在因素（例如，肝细胞或巨噬细胞）的特定细胞类型（例如，在HSF1的条件下，HSF1构成了HSF的情况下，HSF的发育量），以构成HSF的情况下，HSF的发育量是构成hsf1的，HSF的定位突变（HSF）是构成量突变（HSF），以至于HSF的特定细胞类型（例如，肝细胞或巨噬细胞）的发展范围是HSF的突变（HSF）。小鼠）。在AIM 2中，我们将检验以下假设：HSF1缺乏会导致通过HER2/NEU过表达诱导的乳腺肿瘤发生，这是通过修改HER2/NEU与TGF2诱导的抗增殖信号传导过表达引起的Proservival信号之间的平衡发生的。 We will (1) determine the role of Hsf1 in development of mammary tumors using transgenic mouse model expressing Her2/Neu proto-oncogene in mammary epithelium crossed with hsf1-deficient mice, and (2) determine the impact of hsf1 deficiency on mammary tumorigenesis when hsf1 is specifically deleted from epithelial cells before, or after, the initiation of tumorigenesis.我们将使用条件基因敲除技术来检查HSF1缺乏症对HER2/NEU诱导的乳腺癌模型对上皮起源肿瘤的影响。 公共卫生相关性：热休克转录因子1（HSF1）是热休克蛋白（HSP）和其他分子伴侣的主要反式激活因子，通常在人类肿瘤中过表达，从而导致对各种治疗方式的抗性发展。我们已经产生了缺乏HSF1的小鼠模型，并在两个癌症模型中测试了它们的反应。 （1）化学诱导的肝细胞癌（HCC）和（2）一种自发性乳腺肿瘤发生模型，该模型表达针对乳腺上皮的HER2/NEU。我们发现，HSF1缺乏小鼠在两种肿瘤发生模型中均显示出显着降低。在拟议的研究中，我们将研究该肿瘤抑制作用所涉及的潜在机制，当使用上述小鼠模型从肿瘤中删除HSF1，以期预期新型疗法以抑制人类肿瘤中的蛋白质。