The role of the mitochondrial unfolded protein response (UPRmt) in the etiology of breast cancer in young versus elderly women.

衰老和肥胖是患乳腺癌的两个主要危险因素。此外，绝大多数乳房 绝经后妇女的癌症是雌激素受体阳性α（ERα）。 ERα乳腺癌的发生尚不清楚。该应用程序的总体假设是 线粒体生物学在这些观察中起着重要作用。我们的团队专注于线粒体 未折叠蛋白反应（UPRmt）。我们已经确定了线粒体到细胞核的两个平行轴 乳腺癌的治疗其中一个轴由线粒体sirtuin SIRT 3调节， 变老另一种是由ERα调节。我们对普遍定期审议的总体理解是，它是一个 管家功能，以确保线粒体修复和健康，面对癌症中发现的ROS升高 细胞，使线粒体保持其完整性，并产生氨基酸所必需的代谢产物。 酸、脂质和核苷酸的合成;细胞质量增加的基石，肿瘤的特征 增长我们已经在乳腺癌细胞系和诱导型ErbB 2小鼠模型中表征了UPRmt 乳腺癌在体内最近，我们利用这种小鼠模型诱导ErbB 2癌基因， 在年轻和年老的老鼠身上。我们发现，尽管有相同的致癌基因，老年人的肿瘤明显更大， 小鼠此外，我们进行了RNAseq分析，发现了区分这两个群体的遗传特征。 值得注意的是，来自老年小鼠的肿瘤显示SIRT 3减少，但ER和AKT上调。基于 根据这些发现，我们推测，随着SIRT 3在老年女性中的减少，癌基因激活和ROS ERα细胞激活UPRmt的ERα轴以在氧化应激中存活，因此提供了一种抗氧化剂。 对ERα细胞的增殖具有选择性优势。由于卡路里限制（CR）已知会增加 预测SIRT 3、CR的表达影响UPRmt。为了进一步探索这些假设，我们建议： 具体目标1：确定年轻人和非年轻人乳腺肿瘤基因组图谱的区别 与年老的女性相比 具体目标2：测试热量限制是否会影响年轻人乳腺肿瘤的基因组谱 变老，反之亦然。

Aging and obesity are two major risk factors of developing breast cancer. Further, the vast majority of breast cancers in post-menopausal women are estrogen receptor positive alpha (ERα The reason why aging favors the development of ERα breast cancer is not known. The overall hypothesis of this application is that mitochondrial biology plays a fundamental role in these observations. Our group focuses on the mitochondrial unfolded protein response (UPRmt). We have identified two parallel axes of mitochondria to nucleus communication in breast cancer. One axis is regulated by the mitochondrial sirtuin SIRT3, a gene tightly linked to aging. The other is regulated by the ERα. Our overall understanding of the UPRmt is that it acts as a housekeeping function to ensure mitochondrial repair and fitness in face of elevated ROS found in cancer cells, allowing the mitochondria to maintain its integrity and generate the metabolites necessary for amino acids, lipids and nucleotides synthesis; the building blocks of increased cellular mass, characteristic of tumor growth. We have characterized the UPRmt in breast cancer cells lines and in the inducible ErbB2 mouse model of breast cancer in vivo. More recently, we took advantage of this mouse model to induce the ErbB2 oncogene in young and old mice. We found that despite sharing the same oncogene, tumors are significantly larger in old mice. Further, we perform RNAseq analysis and found genetic signatures that distinguish both groups. Notably, tumors derived from old mice show decrease in SIRT3 but up-regulation of ER and AKT. Based on these findings, we hypothesize that as SIRT3 is reduced in older women, upon oncogene activation and ROS production, ERα cells activate the ERα axis of the UPRmt to survive oxidative stress, therefore providing a selective advantage for the proliferation of ERα cells. As calorie restriction (CR) is known to increase the expression for SIRT3, CR is predicted to affect the UPRmt. To further explore these hypotheses, we propose: Specific aim 1: Characterize what distinguish the genomic profiles of mammary tumors derived from young versus old females. Specific aims 2: Test whether calorie restriction affects the genomic profiles of mammary tumors from young to old and vice versa.