Project 2 - Mechanisms linking Cancer Disparities and Metabolic Status

摘要 这项建议解决了非裔美国人(AA)和基底细胞样乳腺癌之间的关系， 肥胖和环境因素通过一种新的代谢调节途径，我们最近已经 图中显示了驱动肿瘤细胞侵袭性行为的因素。将体外研究与患者活检数据相结合 计算分析，我们将表征广泛表达的脂解的调节和功能 在正常和转化的乳腺细胞和组织中刺激的脂蛋白受体(LSR)。LSR是一种 已知的多功能蛋白质介导脂蛋白和疏水环境的内吞作用 肝细胞中的有毒物质，如苯并[α]芘。有趣的是，LSR在细胞交界处丰富，而我们是 首先表明LSR经常被转移到非存活乳腺癌(BRCA)患者的细胞核。 这些观察到的功能和潜在的分子机制尚不清楚。值得注意的是，研究 表明通过饮食获得的有毒物质在体内积累会促进肥胖和炎症，以及 在AAS和低收入社区，有毒物质的生物积累更高。因此，我们假设LSR 表达和/或活性通过调节细胞生物能量学来增强侵袭性BRCA表型， 毒物的生物积累，并改变信号转导和转录组调节，从而促进 癌症差异和患者预后不佳。在支持方面，我们最近证明了LSR增加了BRCA 增殖和迁移，并增强癌症干细胞样和化疗耐药功能。 在低claudin的BRCA细胞系中过表达LSR可以恢复参与转化的基因的表达， 肿瘤发生和紧密连接，从而使这些细胞恢复到其他BRCA亚型。我们的飞行员数据显示 高LSR水平与基底样瘤、AA种族和饮食诱导的肥胖显著相关。我们的 初步数据还表明，膜上定位的LSR介导脂质内吞，从而使 细胞生物能量学，而核LSR结合DNA，并与患者死亡率显著相关 试行BRCA活组织检查。为了推进这些初步研究，我们提出了一种双重方法，包括 描述LSR在驱动攻击性BRCA行为中的作用并确定分子机制 有毒物质的吸收和促进乳房组织的炎症。具体地说，我们的目标是(1)确定LSR- BRCA进展过程中利用的驱动通路和侵略性细胞行为的产生，以及(2) 明确LSR介导BRCA细胞摄取脂质和毒物的机制，以及由此产生的影响 癌症生物能量学和细胞生理学。我们的提议可能会阐明LSR作为一种生物联系 肥胖、炎症、癌症差异和BRCA生理学。从建议中获得的新知识 研究将为饮食对乳腺癌影响的生物学基础提供关键的见解，并可能 确定LSR为新的治疗靶点。

Abstract This proposal addresses the relationship between African American (AA) and basal-like breast cancers, obesity, and environmental factors through a novel metabolically-regulated pathway that we have recently shown drives aggressive tumor cell behaviors. Combining in vitro studies with patient biopsy data and computational analyses, we will characterize the regulation and function of the widely expressed lipolysis stimulated lipoprotein receptor (LSR) in normal and transformed breast cells and tissue. LSR is a multifunctional protein known to mediate the endocytosis of lipoproteins and hydrophobic environmental toxicants such as benzo[α]pyrene in hepatocytes. Intriguingly, LSR is enriched at cell junctions and we are the first to show LSR is frequently translocated to the cell nucleus of non-surviving breast cancer (BrCa) patients. The function and underlying molecular mechanisms for these observations are unknown. Of note, studies show bodily accumulation of toxicants obtained through the diet promotes obesity and inflammation, and toxicant bioaccumulation higher in AAs and in low-income communities. Thus, we hypothesize that LSR expression and/or activity enhances aggressive BrCa phenotypes via modulation of cellular bioenergetics, toxicant bioaccumulation, and altered signal transduction and transcriptome regulation, thereby contributing to cancer disparities and poor patient outcome. In support, we recently demonstrated that LSR increases BrCa proliferation and migration, and enhances cancer stem cell-like and chemotherapeutic resistance features. Overexpression of LSR in a claudin-low BrCa cell line restores expression of genes involved in transformation, tumorigenesis, and tight junctions, thereby reverting these cells to other BrCa subtypes. Our pilot data show high LSR levels are significantly correlated with basal-like tumors, AA ethnicity, and diet-induced obesity. Our preliminary data also demonstrate that membrane-localized LSR mediates lipid endocytosis, thereby shifting cellular bioenergetics, while nuclear LSR binds DNA and was significantly associated with patient mortality in a pilot set of BrCa biopsies. To advance these preliminary studies we propose a dual approach, which includes delineating LSR's role in driving aggressive BrCa behaviors together with defining the molecular mechanisms of toxicant uptake and promotion inflammation in breast tissue. Specifically, we aims to (1) identify the LSR- driven pathways exploited during BrCa progression and the generation of aggressive cell behaviors, and (2) define the mechanisms of LSR-mediated lipid and toxicant uptake in BrCa cells, and the resultant effects on cancer bioenergetics and cell physiology. Our proposal may shed light on LSR as a biological link between obesity, inflammation, cancer disparities, and BrCa physiology. Novel knowledge obtained from the proposed studies will provide critical insight into the biological basis of dietary influences on breast cancer and may identify the LSR as a novel therapeutic target.