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，美国国家癌症研究所提出了一个新的研究重点，以设计严格和创新的研究战略，以解决癌症研究中被确定为国家癌症研究所的“挑衅性问题”的具体问题和悖论。这项研究提案解决了这样一个问题：一个有机体的寿命如何影响癌症发展的分子机制，我们是否可以利用我们对衰老的不断加深的知识来加强癌症的预防或治疗？此外，决定生命周期的途径能否被用来识别潜在的分子生物标记物和靶点，随后可以用来识别对靶向抗癌药物有反应的特定恶性肿瘤组？这项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基因的小鼠会患上雌激素受体(ER)阳性的乳腺癌，这是一种主要在老年女性中观察到的乳腺癌亚型。临床数据还表明，有一组ER阳性的管腔性B乳腺癌表现出部分或完全SIRT3表达缺失。在过去的一年里，该实验室在描述活性氧(ROS)水平、HIF-1a信号和体内允许乳腺癌发生的表型之间的潜在机制关系方面取得了重大进展。因此，有人提出，可能存在一种特定的乳腺癌亚组，其中SIRT3缺失导致ROS和HIF1a增加，这是癌症发生的早期事件，因此，清除ROS分子和/或抑制HIF1a的药物可能被证明加强癌症的预防或治疗。在这项拨款申请中，我们建议，缺乏SIRT3的小鼠是一种新的体内模型，在该模型中，SIRT3水平降低与ROS、HIF-1a、Warburg效应和乳腺恶性肿瘤之间已经建立了良好的联系。我们假设，被认为可以清除或减少细胞内ROS(O2-.)和/或抑制缺氧诱导因子-1�活性将防止sirt3基因敲除小鼠的肿瘤。

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.