Project 2 - Mechanisms linking Cancer Disparities and Metabolic Status

摘要 该提案涉及非裔美国人（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 显示驱动侵袭性肿瘤细胞行为。结合体外研究和患者活检数据， 通过计算分析，我们将描述广泛表达的脂解的调节和功能， 正常和转化乳腺细胞和组织中的刺激脂蛋白受体（LSR）。LSR是一种 已知介导脂蛋白和疏水环境的内吞作用的多功能蛋白质 肝细胞中的苯并[α]芘等毒物。有趣的是，LSR在细胞连接处富集，而我们是细胞连接处的细胞。 首次显示LSR经常转移到非存活乳腺癌（BrCa）患者的细胞核中。 这些观察结果的功能和潜在的分子机制尚不清楚。值得注意的是， 表明通过饮食获得的有毒物质的身体积累会促进肥胖和炎症， 有毒物质的生物积累在AA和低收入社区较高。因此，我们假设LSR 表达和/或活性通过调节细胞生物能量学增强侵袭性BrCa表型， 有毒物质的生物积累，以及改变的信号转导和转录组调节，从而有助于 癌症差异和患者预后差。作为支持，我们最近证明LSR增加BrCa 增殖和迁移，并增强癌症干细胞样和化疗抗性特征。 LSR在低密蛋白BrCa细胞系中的过表达恢复了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为其他BrCa亚型。我们的试点数据显示 高LSR水平与基底细胞样肿瘤、AA种族和饮食诱导的肥胖显著相关。我们 初步数据还表明，膜定位LSR介导脂质内吞作用，从而转移 细胞生物能量学，而核LSR结合DNA，并与患者死亡率显着相关， BrCa活检的试验组。为了推进这些初步研究，我们提出了一种双重方法，其中包括 描述LSR在驱动攻击性BrCa行为中的作用，并定义分子机制 有毒物质的吸收和促进乳腺组织的炎症。具体而言，我们的目标是（1）识别LSR- 在BrCa进展和侵袭性细胞行为的产生期间利用的驱动途径，以及（2） 确定BrCa细胞中LSR介导的脂质和毒物摄取的机制，以及对 癌症生物能量学和细胞生理学。我们的建议可能会揭示LSR作为一种生物联系， 肥胖、炎症、癌症差异和BrCa生理学。新知识从拟议的 这些研究将为饮食对乳腺癌影响的生物学基础提供重要的见解， 将LSR确定为新的治疗靶点。

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.