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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.

肥胖与乳腺癌复发风险增加35%至40%和生存率低有关