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

线粒体未折叠蛋白反应 (UPRmt) 在年轻与老年女性乳腺癌病因学中的作用。

• 批准号: 9927550
• 负责人: DORIS A GERMAIN
• 金额: $ 12.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927550
• 关键词: AF2; Active Sites; Affect; Age; Aging; Amino Acids; Antiestrogen Therapy; Binding; Biogenesis; Biology; Breast Cancer Model; Breast Cancer cell line; Caloric Restriction; Cell Nucleus; Cells; Characteristics; Communication; Cysteine; Deacetylation; Development; Disease; Disulfides; ERBB2 gene; Elderly woman; Ensure; Estrogen Receptor alpha; Estrogen receptor positive; Estrogens; Etiology; Event; Face; Female; Financial compensation; Focus Groups; Genes; Genetic Transcription; Genome; High Fat Diet; Housekeeping; Injections; Knockout Mice; Link; Lipids; Malignant Neoplasms; Mammary Neoplasms; Mind; Mitochondria; Monitor; Mus; Mutation; Obesity; Oncogene Activation; Oncogenes; Oxidative Stress; PI3K/AKT; PTEN gene; Pathway interactions; Pattern; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Postmenopause; Production; Proteins; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Reporting; Resistance; Risk Factors; Role; SOD2 gene; Signal Pathway; Signal Transduction; Sirtuins; Site; Source; Stress; Subfamily lentivirinae; Testing; Tumor-Derived; Up-Regulation; Woman; base; cancer cell; erbB-2 Receptor; fitness; genetic signature; genome-wide analysis; genomic profiles; in vivo; malignant breast neoplasm; mitochondrial fitness; mouse model; neoplastic cell; nucleotide metabolism; older women; overexpression; oxidation; programs; repaired; response; transcription factor; transcriptome sequencing; tumor; tumor growth

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.

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 绝经后女性的癌症是雌激素受体阳性α（ERα）衰老的原因 ERα 乳腺癌的发展尚不清楚。该应用程序的总体假设是 线粒体生物学在这些观察中发挥着基础作用。我们小组专注于线粒体 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 乳腺癌中的沟通。一个轴由线粒体 Sirtuin SIRT3 调节，这是一种紧密相连的基因 到老化。另一个受ERα调节。我们对普遍定期审议的总体理解是，它充当 面对癌症中发现的活性氧升高，确保线粒体修复和健康的管家功能 细胞，使线粒体保持其完整性并产生氨基酸所需的代谢物 酸、脂类和核苷酸的合成；细胞质量增加的组成部分，这是肿瘤的特征 生长。我们对乳腺癌细胞系和诱导型 ErbB2 小鼠模型中的 UPRmt 进行了表征 体内乳腺癌。最近，我们利用这种小鼠模型来诱导 ErbB2 癌基因 在年轻和年老的小鼠中。我们发现，尽管共享相同的癌基因，但老年人的肿瘤明显更大 老鼠。此外，我们进行 RNAseq 分析并发现了区分这两个群体的遗传特征。 值得注意的是，来自年老小鼠的肿瘤显示 SIRT3 减少，但 ER 和 AKT 上调。基于 根据这些发现，我们假设随着癌基因激活和 ROS 在老年女性中 SIRT3 的减少 产生时，ERα细胞激活UPRmt的ERα轴以抵抗氧化应激，从而提供 ERα细胞增殖的选择性优势。众所周知，热量限制 (CR) 会增加 SIRT3 的表达，预计 CR 会影响 UPRmt。为了进一步探讨这些假设，我们建议： 具体目标 1：表征源自年轻乳腺肿瘤的基因组图谱的区别 与老年女性相比。 具体目标2：测试热量限制是否影响年轻时乳腺肿瘤的基因组图谱 到旧，反之亦然。