ROS and HIFa as molecular targets for chemoprevention in Sirt3 -/- breast cancers

描述（由申请人提供）：个性化癌症治疗的一个想法是确定将从特定治疗策略中受益的特定癌症患者亚群。最近，NCI提出了一个新的研究重点，即设计严谨和创新的研究策略，以解决癌症研究中的具体问题和悖论，即NCI的“挑衅性问题”。这项研究计划解决了这样一个问题：“生物体的寿命如何影响癌症发展的分子机制？我们能否利用我们对衰老的深入了解来加强癌症的预防或治疗？”此外，指导生命周期的途径能否用于识别潜在的分子生物标志物和靶标，随后可用于识别将对靶向抗癌药物产生反应的特定恶性肿瘤组？这一建议清楚地解决了这个问题，因为我们之前已经表明，缺乏线粒体Sirt3基因的小鼠会产生雌激素受体（ER）阳性的乳腺肿瘤，这是一种主要见于老年女性的乳腺癌亚型。临床数据还表明，有一个ER阳性B型人乳腺癌亚组表现出SIRT3部分或完全表达缺失。去年，该实验室在描述活性氧（ROS）水平、HIF-1a信号和允许乳腺癌发生的体内表型之间的潜在机制关系方面取得了重大进展。因此，我们提出可能存在一个特定的乳腺癌亚组，其中Sirt3的缺失导致ROS和HIF1a的增加，这是癌变的早期事件，因此，清除ROS分子和/或抑制HIF1a的药物可能被证明可以加强癌症的预防或治疗。在这项拨款申请中，我们提出缺乏Sirt3的小鼠是一种新的体内模型，用于研究Sirt3水平下降与ROS、HIF-1a、Warburg效应和乳腺恶性肿瘤之间已经建立的联系。我们假设，被认为清除或减少细胞ROS （O2-）和/或抑制HIF-1¿活性的药物可以预防Sirt3敲除小鼠的肿瘤。

DESCRIPTION (provided by applicant): One idea of personalized cancer therapy is to identify specific subgroup of cancer patients that will benefit from specific therapeutic strategy. Recently the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research identified as the NCI's "Provocative Questions". This research proposal addresses one such question "How does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In addition, can the pathways that direct life span be used to identify potential molecular biomarkers and targets that can subsequently be used to identify specific groups of malignancies that will respond to targeted anticancer agents? This proposal clearly addresses this question in that we have previously shown that mice lacking mitochondrial Sirt3 gene develop estrogen receptor (ER) positive mammary tumors, a subtype of breast cancer predominantly observed in older women. Clinical data also suggest that there is a subgroup of ER positive luminal B human breast cancers that exhibit partial or complete loss of SIRT3 expression. In the last year the laboratory has made significant progress in delineating the underlying mechanistic relationship between reactive oxygen species (ROS) levels, HIF-1a signaling, and an in vivo phenotype permissive for breast carcinogenesis. Thus, it is proposed that there may be a specific subgroup of breast malignancies where loss of Sirt3 results in increased ROS and HIF1a that are early events in carcinogenesis and as such, agents that scavenge ROS molecules and/or inhibit HIF1a may prove to enhance cancer prevention or treatment. In this grant application we propose that mice lacking Sirt3 are a novel in vivo model in which to investigate the well established connection between decreased SIRT3 levels and ROS, HIF-1a, the Warburg effect, and breast malignancies. We hypothesize that agents thought to scavenge or decrease cellular ROS (O2-.) and/or inhibit HIF-1¿ activity will prevent tumors in Sirt3 knockout mice.