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.

女性之间的乳房衰老率不同。此外，老年妇女倾向于发展雌激素 受体α（ERα）阳性乳腺癌亚型，所需的较低的激素水平。我们的初步数据 迫使我们假设线粒体遗传学会改变乳房的衰老率，并影响亚乳房 乳腺癌的类型。乳腺导管树由腔激素灵敏（HS），ERα阳性组成 细胞以及腔牙槽（AV）和基本细胞均为ERα阴性。最近的SCRNASEQ分析 揭示了在基本和腔内AV细胞中，线粒体功能随着年龄的增长而下降，但这种下降 相反，腔内HS细胞似乎上调了未折叠的蛋白 内质网（Uprer）的响应。将船体与线粒体紧密相互连接 UPR（UPRMT）。我们的小组已将ERα和线粒体Sirtuin-3（SIRT3）确定为主要参与者 UPRMT。尽管ERα的水平不会随着年龄的增长而波动，但在大多数个体中，SIRT3水平随着 年龄。因此，我们的核心假设是在基本和 衰老上的腔内AV细胞可能是由于UPRMT的SIRT3轴的下降。但是，在腔内 HS细胞通过通过ERα轴维持线粒体功能时观察到这种下降 UPRMT。我们假设腔HS细胞通过衰老，维持线粒体功能的能力， 让他们能够在转化中生存并解释老年人对ERα阳性乳腺癌的选择性偏差 女性。此外，我们在衍生乳腺肿瘤的年轻和老年女性上进行了RNASEQ， 源自年轻女性和老年女性的腔内HS细胞。我们发现急诊室的标记？ UPRMT和UPRER的轴在老年腔HS细胞中专门上调。这个观察结果 建议急诊室的转录程序？可能会因衰老而改变。我们假设 衰老期间ROS的增加和恐怖的下降改变了ERα的转录程序。 此外，SIRT3的下降速度随着个人之间的年龄变化。同样，我们发现 SIRT3在具有相同核基因组（BL/6）的BL/6NZB和BL/6C57小鼠之间不同，但不同 mtdna; （C57或NZB）。因此，这意味着UPRMT的SIRT3轴的下降速率 基于mtDNA单倍型的年龄差异。最后，我们假设虽然BL/6C57小鼠（低SIRT3）将 在BL/6NZB女性（高SIRT3）中，仅在衰老上发展ERα阳性乳腺肿瘤，既 嗯？将观察到阳性乳腺肿瘤。为了检验这些假设，我们提出以下目的： 特定目的1：分析ERα阳性腔乳中的UPRMT和UPRER以及ERα转录组 细胞超过衰老。特定目标2：在BL/6C57中对乳腺进行乳腺的SCRNASEQ分析 和BL/6NZB小鼠。特定目标3：比较BL/6C57和BL/6NZB之间乳腺肿瘤的子类型 小鼠衰老。我们建议在绝经前和绝经后以及古老的小鼠中进行这些分析。