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.

乳房的老化速度在女性之间是不同的。此外，老年妇女往往发展雌激素 受体α（ERα）阳性乳腺癌亚型，尽管激素水平较低。我们的初步数据 迫使我们假设线粒体遗传学改变了乳房的衰老速度，并影响了亚 乳腺癌的类型乳腺导管树由管腔激素敏感型（HS）、ERα阳性型（ERα +）、 细胞以及腔肺泡（AV）和基底细胞均为ERα阴性。最近的scRNAseq分析 揭示了在基底和腔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Luminal HS细胞中未观察到。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与线粒体紧密相连， 普遍定期审议（UPRmt）。我们的研究小组已经确定ERα和线粒体sirtuin-3（SIRT 3）是细胞凋亡的关键参与者。 UPRmt.虽然ERα的水平不随年龄波动，但在大多数个体中，SIRT 3水平随着年龄的增长而下降。 年龄因此，我们的中心假设是，在基底节和基底节中观察到的线粒体功能下降， 管腔AV细胞的过度老化可能是由于UPRmt的SIRT 3轴的下降。然而，在管腔中， HS细胞没有观察到这种下降，因为它们通过线粒体的ERα轴维持线粒体功能。 UPRmt.我们假设管腔HS细胞在衰老过程中维持线粒体功能的能力， 使它们能够在转化中存活下来，并解释了老年人对ERα阳性乳腺癌的选择性偏见。 妇女此外，我们对年轻和老年女性来源的乳腺肿瘤进行了RNAseq， 建立了来自年轻和老年女性的管腔HS细胞。我们发现急诊室的标记？ UPRmt和UPRER轴在衰老的管腔HS细胞中特异性上调。该观察结果 提示ER？可能会随着年龄的增长而改变我们假设 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，SIRT 3随年龄下降的速率在个体之间存在差异。同样，我们发现， BL/6 NZB和BL/6C 57小鼠具有相同的核基因组（BL/6），但不同的SIRT 3 mtDNA;（C57或NZB）。因此，这意味着，UPRmt的SIRT 3轴的下降率与 不同年龄段的mtDNA单倍型不同。最后，我们假设BL/6C 57小鼠（低SIRT 3） 在BL/6 NZB雌性（高SIRT 3）中，随着年龄的增长，仅发生ERα阳性乳腺肿瘤， 急诊室？将观察到阳性乳腺肿瘤。为了验证这些假设，我们提出了以下目标： 具体目的1：ERα阳性乳腺癌组织中UPRmt和UPER及ERα转录组的分析 细胞过度老化具体目标2：在BL/6C 57中进行乳腺过老化的scRNAseq分析 和BL/6 NZB小鼠。具体目标3：比较BL/6C 57和BL/6 NZB之间的乳腺肿瘤亚型 老鼠过老我们建议在绝经前、绝经后和绝经后以及老年小鼠中进行这些分析。