Roles of Hsp47 in Breast Cancer Progression

Hsp47 在乳腺癌进展中的作用

基本信息

批准号：
10701814
负责人：
Ren Xu
金额：
$ 35.61万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-03 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701814
关键词：
3-Dimensional Adipocytes Adipose tissue Binding Bioinformatics Biological Assay Blood Platelets Breast Breast Cancer Risk Factor Breast cancer metastasis Cardiovascular Diseases Co-Immunoprecipitations Coculture Techniques Collagen Data Deposition Diabetes Mellitus Epithelium Extracellular Matrix Fibrosis Funding Genetic Transcription High Fat Diet Human Infiltration Inflammation Knockout Mice Knowledge Link Macrophage Malignant Neoplasms Mammary Neoplasms Mesenchymal Modeling Molecular Molecular Chaperones Mus Nature Neoplasm Metastasis Non obese Obesity Obesity associated cancer Pathologist Pathway interactions Patients Play Positioning Attribute Proteins Proteomics Recurrent Malignant Neoplasm Regulation Repression Research Role Scheme Signal Transduction Surface Plasmon Resonance Testing Tissue Sample Tissues Transgenic Organisms Tumor Tissue adipocyte differentiation asporin breast cancer progression cancer cell cancer recurrence carcinogenesis diet-induced obesity digital experimental study immune cell infiltrate in vivo inhibitor insight malignant breast neoplasm mammary gland development mouse model multidisciplinary nano-string novel obesity development recruit second harmonic generation imaging single-cell RNA sequencing stemness survival outcome tissue culture tumor growth tumor progression

项目摘要

Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and poor survival outcomes. One feature of obese adipose tissue is the excess extracellular matrix (ECM) deposition/remodeling in the form of fibrosis. However, function and regulation of obesity-related ECM deposition/remodeling in cancer progression largely remain to be determined. We recently identified Hsp47, a chaperone protein facilitating collagen secretion, as a hub of the ECM transcription network. Our new data showed that Hsp47 was highly expressed in adipose tissue. Importantly, increased Hsp47 expression in human and mouse adipose tissues was significantly associated with obesity development. We found that adipocyte-specific deletion of Hsp47 was sufficient to suppress high fat diet (HFD)-induced obese and mammary tumor growth, which is accompanied by reduced collagen deposition/alignment and macrophage infiltration in adipose tissue. The overall objective of this proposal is to define the mechanism by which adipocyte Hsp47 promotes obese-related fibrosis and breast cancer progression and to explore the value of Hsp47 as a potential target to suppress obesity- associated cancer progression. Using unbiased proteomics analysis, we identified asporin as a new target of Hsp47 in adipocytes. Based on these data, the central hypothesis of this proposal is that Hsp47 induces obesity-related fibrosis by facilitating asporin secretion in adipocytes, and subsequently enhances adipocyte plasticity and breast cancer progression. Following aims are proposed to test our hypothesis: Aim 1. Elucidate the molecular mechanism by which adipocyte Hsp47 induces obesity- and cancer-associated ECM remodeling; Aim 2. Determine how Hsp47 regulates obesity-associated and cancer-induced adipocyte plasticity; Aim 3. Define the potential of targeting Hsp47 to suppress obesity- associate fibrosis, inflammation, and breast cancer progression/metastasis.

肥胖与乳腺癌复发和生存不良的风险增加 35% 至 40% 有关结果。肥胖脂肪组织的特征之一是细胞外基质（ECM）过多以纤维化形式沉积/重塑。然而，肥胖相关 ECM 的功能和调节癌症进展中的沉积/重塑很大程度上仍有待确定。我们最近确定 Hsp47 是一种促进胶原蛋白分泌的伴侣蛋白，是 ECM 转录网络的枢纽。我们的新数据表明 Hsp47 在脂肪组织中高表达。重要的是，Hsp47 增加人类和小鼠脂肪组织中的表达与肥胖显着相关发展。我们发现脂肪细胞特异性删除 Hsp47 足以抑制高脂肪饮食（HFD）引起的肥胖和乳腺肿瘤生长，伴随着胶原蛋白的减少脂肪组织中的沉积/排列和巨噬细胞浸润。本次活动的总体目标该提案旨在明确脂肪细胞 Hsp47 促进肥胖相关纤维化的机制，以及乳腺癌进展并探索 Hsp47 作为抑制肥胖潜在靶点的价值 - 相关的癌症进展。通过无偏见的蛋白质组学分析，我们确定阿孢菌素是一种新的脂肪细胞中 Hsp47 的靶标。基于这些数据，该提案的中心假设是 Hsp47 通过促进脂肪细胞中阿孢菌素的分泌来诱导肥胖相关的纤维化，随后增强脂肪细胞可塑性和乳腺癌进展。提出以下目标来测试我们的假设：目的1.阐明脂肪细胞Hsp47诱导肥胖的分子机制癌症相关的 ECM 重塑；目标 2. 确定 Hsp47 如何调节肥胖相关和癌症诱导的脂肪细胞可塑性；目标 3. 确定靶向 Hsp47 抑制肥胖的潜力 - 与纤维化、炎症和乳腺癌进展/转移相关。