SIRT3 is a Mitochondrial Tumor Suppressor in ER/PR Positive Mammary Tumors

描述(申请人提供)：肿瘤学中的一个基本观察是，随着年龄的增长，恶性肿瘤的发生率显着增加，这表明控制长寿的细胞过程与癌症的发展之间存在潜在的机制联系。在这方面，最近在酿酒酵母和线虫中发现了对长寿(或衰老)起关键作用的基因，这些基因的人类同源物被称为Sirtuin基因家族。因此，我们假设sirtuin基因可能作为保真基因发挥作用，而sirtuin功能的丧失可能发生在衰老过程中，从而为包括癌症发生在内的与年龄相关的疾病创造了允许的细胞环境。为了解决这个问题，我们在四年前构建了线粒体定位SIRT3蛋白基因缺失的小鼠。我们的实验室最近表明，这些小鼠患上雌激素和孕激素受体(ER/PR)阳性的乳腺癌，这是老年女性常见的癌症亚型。这些实验结果表明，SIRT3是第一个被鉴定的基因组表达的、线粒体定位的肿瘤抑制基因(TS)，也表明线粒体衰老基因与细胞环境或允许发生乳腺肿瘤的表型之间存在遗传关系。研究还表明，细胞内的活性氧物种(ROS)以及线粒体超氧化物歧化酶基因(MnSOD)--主要的超氧化物歧化蛋白--在衰老和癌症发生中发挥了作用。在这方面，我们的初步结果表明，在SIRT3基因敲除的小鼠中，超氧化物歧化发生了变化。因此，我们假设，被认为可以防止衰老的细胞效应和细胞内ROS积累的药物，如CR，将在SIRT3基因敲除小鼠中预防肿瘤。此外，使用一系列免疫组织化学染色来表征小鼠导管细胞的病理、组织学和氧化还原变化，以开始确定在SIRT3基因敲除小鼠中观察到的致癌允许表型的潜在体内机制。

DESCRIPTION (provided by applicant): A fundamental observation in oncology is that the rate of malignancies increases significantly as a function of age suggesting a potential mechanistic link between the cellular process governing longevity and the development of cancers. In this regard, the genes that play a critical role in longevity (or aging) have recently been characterized in Saccharomyces cerevisiae and C. elegans and the human homologs of these genes are referred to as the Sirtuin gene family. Thus, we hypothesized that the sirtuin genes might function as fidelity genes and loss sirtuin function, which might occur during aging, would create cellular environment permissive for age related illness including carcinogenesis. To address this idea we constructed mice four years ago that have the mitochondrial localized SIRT3 protein genetically deleted. Our laboratory has recently shown that these mice develop estrogen and progesterone receptor (ER/PR) positive mammary tumors that are a subtype of cancer commonly observed in older women. The results of these experiments suggest that SIRT3 is the first identified genomic expressed, mitochondrial localized tumor suppressor (TS) and also suggests a genetic relationship between a mitochondrial aging gene and a cellular environment or phenotype permissive for development of mammary tumors. It has also been shown that intracellular reactive oxygen species (ROS), as well as the mitochondrial superoxide dismutase gene (MnSOD) - the primary superoxide scavenging protein - play a role in aging and carcinogenesis. In this regard, our preliminary results demonstrated altered superoxide in our SIRT3 knockout mice. Thus, we hypothesize that agents thought to prevent the cellular effects of aging and the accumulation of intracellular ROS, such as CR, will be prevent tumors in the SIRT3 knockout mice. In addition, use a series of immunohistochemical staining to characterize the pathological, histology, and redox changes in the murine ductal cells to begin to identify the potential underlying in vivo mechanism of carcinogenic permissive phenotype observed in the SIRT3 knockout mice.