Understanding the influence of Mitochondrial DNA haplotypes on breast aging and cancer

了解线粒体 DNA 单倍型对乳腺癌衰老和癌症的影响

• 批准号: 10591676
• 负责人: DORIS A GERMAIN
• 金额: $ 48.47万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591676
• 关键词: Affect; African; Age; Aging; Agreement; Alveolar; Alveolar Cell; Automobile Driving; Basal Cell; Breast; Breast Cancer Model; Cells; Centenarian; Complex; Data; ERBB2 gene; Elderly; Endoplasmic Reticulum; Estrogen Receptor alpha; Estrogens; Etiology; European; Evolution; Female; Genetic; Genetic Transcription; Genome; Genotype; Haplotypes; Hormonal; Hormones; Individual; Injections; Malignant Neoplasms; Mammary Duct; Mammary Neoplasms; Mammary gland; Mediating; Menopause; Mitochondria; Mitochondrial DNA; Monitor; Mouse Mammary Tumor Virus; Mus; Nuclear; Oncogenes; Oxidative Stress; Perimenopause; Population; Postmenopause; Predisposition; Premenopause; Progesterone; Proteins; Regulation; Retroviridae; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Sirtuins; Stress; Testing; Transgenic Mice; Transgenic Organisms; Trees; Woman; aged; cancer subtypes; gain of function; high risk; loss of function; malignant breast neoplasm; mammary; mitochondrial fitness; mouse model; older women; preservation; programs; promoter; receptor; response; transcriptome; transcriptome sequencing; transgene expression; tumor; young adult

The rate of aging of the breast differs between women. Further, older women tend to develop estrogen receptor alpha (ERα) positive breast cancer sub-type, despite lower hormonal levels. Our preliminary data compel us to hypothesize that mitochondrial genetics alters the rate of aging of the breast and impacts the sub- type of breast cancer. The mammary ductal tree is composed of luminal hormone sensitive (HS), ERα positive cells as well as luminal alveolar (AV) and basal cells that are both ERα negative. A recent scRNAseq analysis revealed that in both the basal and luminal AV cells, mitochondrial function declines with age but this decline was not observed in luminal HS cells. Rather, the luminal HS cells seem to up-regulate of the unfolded protein response of the endoplasmic reticulum (UPRER). The UPRER is closely interconnected with the mitochondrial UPR (UPRmt). Our group has identified the ERα and the mitochondrial sirtuin-3 (SIRT3) as key players of the UPRmt. While the level of the ERα does not fluctuate with age, in most individuals, SIRT3 levels decrease with age. Therefore, our central hypothesis is that the decline in mitochondrial function observed in the basal and luminal AV cells over aging may be due to the decline in the SIRT3 axis of the UPRmt. However, in the luminal HS cells this decline is not observed as they maintain mitochondrial function through the ERα axis of the UPRmt. We hypothesize that the ability of luminal HS cells to maintain mitochondrial function through aging, allow them to survive transformation and explains the selective bias toward ERα positive breast cancer in older women. Further, we performed RNAseq on the young and old-females derived mammary tumors and established luminal HS cells derived from both young and aged females. We found that markers of the ER? axis of the UPRmt and UPRER are up-regulated specifically in the aged luminal HS cells. This observation suggests that the transcriptional program of the ER? may be altered by aging. We hypothesize that the increase in ROS and the decline in hormones during aging alter the transcriptional program of the ERα. Further, the rate of decline in SIRT3 with age varies between individuals. Likewise, we found that the levels of SIRT3 differ between the BL/6NZB and BL/6C57 mice which have the same nuclear genome (BL/6), but different mtDNA; (C57 or NZB). Therefore, the implication is that the rate of decline of the SIRT3 axis of the UPRmt with age differs based on mtDNA haplotypes. Lastly, we hypothesize that while BL/6C57 mice (low SIRT3) will develop exclusively ERα positive mammary tumor over aging, in BL/6NZB females (high SIRT3) both basal and ER? positive mammary tumors will be observed. To test these hypotheses, we propose the following aims: Specific aim 1: Analyze of the UPRmt and UPRER and the ERα transcriptome in ERα positive luminal mammary cells over aging. Specific aim 2: Perform scRNAseq analysis of the mammary gland over aging in BL/6C57 and BL/6NZB mice. Specific aim 3: Compare the sub-types of mammary tumors between BL/6C57 and BL/6NZB mice over aging. We propose to do these analyses in pre-, peri- and post-menopausal as well as elderly mice.

此外，女性的乳房衰老速度也有所不同，老年女性往往会产生雌激素。 尽管我们的初步数据较低，但受体α（ERα）阳性乳腺癌亚型。 迫使我们重新认识到线粒体遗传学改变了乳房的衰老速度并影响了亚健康 乳腺癌类型由管腔激素敏感 (HS)、ERα 阳性组成。 最近的 scRNAseq 分析显示，ERα 阴性的细胞以及管腔肺泡 (AV) 和基底细胞。 研究表明，在基底和管腔 AV 细胞中，线粒体功能随着年龄的增长而下降，但这种下降 在管腔 HS 细胞中没有观察到，相反，管腔 HS 细胞似乎上调了未折叠的蛋白质。 内质网反应 (UPRER) UPRER 与线粒体密切相关。 我们的小组已确定 ERα 和线粒体 Sirtuin-3 (SIRT3) 是 UPR (UPRmt) 的关键参与者。 UPRmt。虽然 ERα 的水平不随年龄波动，但在大多数个体中，SIRT3 水平随着年龄的增长而下降。 因此，我们的中心假设是基础和线粒体功能的下降。 管腔 AV 细胞过度老化可能是由于 UPRmt 的 SIRT3 轴下降所致。 HS 细胞没有观察到这种下降，因为它们通过 ERα 轴维持线粒体功能。 UPRmt。我们努力解决管腔 HS 细胞在衰老过程中维持线粒体功能的能力， 让他们能够在转化中幸存下来，并解释老年人对 ERα 阳性乳腺癌的选择性偏见 此外，我们对年轻和老年女性的乳腺肿瘤进行了 RNAseq 分析。 我们建立了来自年轻和老年女性的管腔 HS 细胞，我们发现了 ER？ UPRmt 和 UPRER 轴在老化的管腔 HS 细胞中特别上调。 表明 ER 的转录程序可能会因衰老而改变。 衰老过程中 ROS 的增加和激素的减少改变了 ERα 的转录程序。 此外，SIRT3 随着年龄的增长而下降的速度因人而异，同样，我们发现 SIRT3 的水平也存在差异。 SIRT3 在 BL/6NZB 和 BL/6C57 小鼠之间存在差异，它们具有相同的核基因组 (BL/6)，但不同 mtDNA；（C57或NZB）因此，这意味着UPRmt的SIRT3轴的下降率。 最后，我们发现 BL/6C57 小鼠（低 SIRT3）的年龄会有所不同。 在 BL/6NZB 女性（高 SIRT3）中，随着年龄的增长，仅发生 ERα 阳性乳腺肿瘤，无论是基础还是 为了检验这些假设，我们提出以下目标： 具体目标1：分析ERα阳性乳腺中的UPRmt和UPRER以及ERα转录组 具体目标 2：在 BL/6C57 中对乳腺过度老化进行 scRNAseq 分析。 和BL/6NZB小鼠具体目的3：比较BL/6C57和BL/6NZB之间的乳腺肿瘤亚型。 我们建议对绝经前、围绝经期和绝经后以及老年小鼠进行这些分析。