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

描述（由申请人提供）：肿瘤学中的一项基本观察结果是，恶性肿瘤的发生率随年龄的增加而显著增加，这表明控制寿命的细胞过程与癌症发生之间存在潜在的机制联系。在这方面，在长寿（或衰老）中起关键作用的基因最近已经在酿酒酵母和C。线虫和这些基因的人类同源物被称为Sirtuin基因家族。因此，我们假设沉默调节蛋白基因可能作为保真度基因发挥作用，并且在衰老期间可能发生的沉默调节蛋白功能丧失将产生允许年龄相关疾病包括致癌的细胞环境。为了解决这个问题，我们在四年前构建了线粒体定位SIRT 3蛋白基因缺失的小鼠。我们的实验室最近表明，这些小鼠发展雌激素和孕激素受体（ER/PR）阳性乳腺肿瘤，这是一种常见于老年妇女的癌症亚型。这些实验的结果表明，SIRT 3是第一个鉴定的基因组表达的线粒体定位的肿瘤抑制因子（TS），并且还表明线粒体衰老基因与允许乳腺肿瘤发展的细胞环境或表型之间的遗传关系。研究还表明，细胞内活性氧（ROS）以及线粒体超氧化物歧化酶基因（MnSOD）-主要的超氧化物清除蛋白-在衰老和致癌中发挥作用。在这方面，我们的初步结果表明，在我们的SIRT 3基因敲除小鼠改变超氧化物。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，将预防SIRT 3敲除小鼠中的肿瘤。此外，使用一系列免疫组织化学染色来表征小鼠导管细胞中的病理学、组织学和氧化还原变化，以开始鉴定在SIRT 3敲除小鼠中观察到的致癌容许表型的潜在潜在体内机制。

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.