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

描述（由申请人提供）：肿瘤学的一个基本观察是，恶性肿瘤的发病率随着年龄的增长而显著增加，这表明在控制寿命的细胞过程和癌症的发展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在酿酒酵母和秀丽隐杆线虫中被鉴定出来，这些基因的人类同源基因被称为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，而在衰老过程中可能发生的sirtuin功能丧失，将创造有利于年龄相关疾病（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SIRT3蛋白基因缺失的小鼠。我们实验室最近的研究表明，这些小鼠会产生雌激素和孕激素受体（ER/PR）阳性的乳腺肿瘤，这是一种常见于老年女性的癌症亚型。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肿瘤抑制因子（TS），也表明线粒体衰老基因与乳腺肿瘤发展的细胞环境或表型之间存在遗传关系。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——在衰老和致癌过程中发挥作用。在这方面，我们的初步结果表明SIRT3敲除小鼠的超氧化物发生了改变。因此，我们假设，被认为可以防止细胞衰老和细胞内ROS积累的药物，如CR，将在SIRT3敲除小鼠中预防肿瘤。此外，利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，开始确定SIRT3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. PUBLIC HEALTH RELEVANCE: The overarching theme of this proposal is based on one of the fundamental observations in oncology showing that the rate of malignancies increases significantly with age. Recently, it was shown that the Sirtuin gene family may determine aging (longevity). Thus, we hypothesize a genetic and biochemical relationship between the mitochondrial sirtuin, SIRT3, metabolism, and ER/PR positive breast cancers.