Roles of Hsp47 in Breast Cancer Progression

肥胖与乳腺癌复发风险增加35%至40%和生存率差有关 结果。肥胖脂肪组织的一个特征是过量的细胞外基质（ECM） 以纤维化的形式沉积/重塑。然而，肥胖相关ECM的功能和调节 在癌症进展中的沉积/重塑在很大程度上仍有待确定。我们最近发现 Hsp 47是一种促进胶原分泌的分子伴侣蛋白，是ECM转录网络的枢纽。 我们的新数据表明，Hsp 47在脂肪组织中高度表达。更重要的是，Hsp 47增加 在人类和小鼠脂肪组织中的表达与肥胖显著相关 发展我们发现，脂肪细胞特异性的Hsp 47缺失足以抑制高脂血症。 饮食（HFD）诱导的肥胖和乳腺肿瘤生长，伴随着胶原蛋白减少 脂肪组织中的沉积/排列和巨噬细胞浸润。本报告的总体目标 这项研究的目的是确定脂肪细胞Hsp 47促进肥胖相关纤维化的机制， 乳腺癌进展，并探索Hsp 47作为抑制肥胖的潜在靶点的价值- 相关的癌症进展。使用无偏蛋白质组学分析，我们确定asporin作为一个新的 脂肪细胞中Hsp 47靶向。根据这些数据，该提案的中心假设是， Hsp 47通过促进脂肪细胞中asporin的分泌诱导肥胖相关的纤维化， 增强脂肪细胞可塑性和乳腺癌进展。提出了以下目标来测试我们的 假设：目标1。阐明脂肪细胞Hsp 47诱导肥胖的分子机制， 癌症相关ECM重塑; Aim 2.确定Hsp 47如何调节肥胖相关的 癌症诱导的脂肪细胞可塑性;目的3.定义靶向Hsp 47抑制肥胖的潜力- 与纤维化、炎症和乳腺癌进展/转移相关。

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.