Mitochondrial dysfunction and chronic stress intersect as mechanisms driving breast cancer racial disparities

线粒体功能障碍和慢性压力交叉作为驱动乳腺癌种族差异的机制

基本信息

批准号：
10673729
负责人：
Lisa Sale Shock
金额：
$ 17.78万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673729
关键词：
3-Dimensional Accounting Acute Adenine Affect African American Automobile Driving Bioenergetics Biogenesis Biological Biological Factors Biology Blood Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer cell line Breast Cancer gene Breast Carcinogenesis Cancer Gene Mutation Cardiovascular system Cell Culture Techniques Cell Line Cell Respiration Characteristics Chronic Chronic stress Complex Cytosine DNA Methylation DNA Sequence Alteration DNA copy number Defect Detection Development Disease Disparity Electronic Health Record Endocrine Enzymes Epidemiology Epigenetic Process Ethnic Population Event Exposure to Gene Mutation Glucocorticoid Receptor Glucocorticoids Goals Hormones Immune system In Vitro Incidence Individual Differences Intervention Knowledge Link Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Measures Mediating Mediator Metabolic Metastatic/Recurrent Methylation Mitochondria Mitochondrial DNA Modeling Modification Molecular Mutation Mutation Analysis Normal Cell Outcome Oxidative Phosphorylation Pathway interactions Patients Phenotype Physiological Population Psychosocial Stress Recurrence Regulation Risk Factors Role Secondary to Series Severities Shock Signal Pathway Socioeconomic Status Stress System Tumor Tissue Western Blotting Woman aggressive breast cancer allostatic load antagonist biological adaptation to stress black women cancer diagnosis cancer health disparity cancer subtypes caucasian American clinical phenotype genome-wide global health health record improved insight lifestyle intervention malignant breast neoplasm metabolomics mitochondrial DNA mutation mitochondrial dysfunction mortality mutational status patient stratification psychosocial racial disparity racial population screening social social factors stressor treatment strategy tumor

项目摘要

Project Summary/Abstract PI: Shock, Lisa S. Breast cancer represents an estimated 30% of all new cancer diagnoses in women and claimed over 40,000 lives in 2020 alone (1). African American (AA) women are disproportionately affected; AA women are more likely to develop aggressive triple-negative subtypes, and suffer from recurrent or metastatic disease (2-4), and mortality rates among AA breast cancer patients remain highest compared to all other race/ethnicity groups (2- 5). The biological and non-biological factors underlying these disparities are complex and largely unknown. Allostatic load (AL) is an effective measure of physiologic dysregulation secondary to stress and is often used to quantify the physiological burden of breast cancer (10-13). AL has been shown to be positively associated with breast cancer risk and more aggressive phenotypes among AA women, but not among white women (10,12-14). These findings support the notion that social and biological factors contribute to breast cancer features and survival. Mitochondrial DNA (mtDNA) abnormalities including mutations, deletions, and copy number changes, are frequent events in cancer. A recent pan-cancer study found that tumors from AA patients were enriched for mitochondrial OXPHOS and contained more mitochondria than the same cancers from white Americans (15). Increased mitochondrial DNA (mtDNA) copy number in the blood of breast cancer patients was recently shown to be positively associated with AL, suggesting that mtDNA content is a possible mediator linking higher AL and aggressive breast tumor characteristics (10). MtDNA is epigenetically modified by cytosine and adenine methylation, and this represents a powerful mechanism for environmental regulation of mitochondrial function (Fig 1, 16-19). While genome-wide DNA methylation changes have been linked to breast tumor characteristics, the role of mtDNA methylation in breast cancer incidence/mortality remains unexplored. The studies proposed here aim to better understand the social and biological basis for why black women are disproportionately affected by more severe breast cancer subtypes and higher mortality rates. Epidemiological, molecular and metabonomic approaches are proposed to examine the effects of chronic stress on mitochondrial biology as they contribute to breast cancer disparities. First, we will investigate the impact of AL on mitochondrial biology in breast tumor tissues from both AA and white patients. We will determine the extent to which AL is associated with mitochondrial abnormalities, including mtDNA mutations/deletions, copy number, epigenetic modifications and mitochondrial enzyme defects. Second, we will evaluate the effects of stress hormones on mitochondrial function in a panel of breast cancer and normal cell lines cultured in 2- and 3-dimensions. Stress-induced changes to mtDNA content, epigenetic modification and metabolic changes will be quantified. These approaches will explore the interplay between psychosocial risk factors and biological pathways underlying disparities in breast cancer incidence and severity among AA women, with the goal of better informing patient stratification and treatment strategies.

项目摘要/摘要PI：Shock，Lisa S. 乳腺癌估计占女性所有新癌症诊断的30％，声称超过40,000 仅2020年就生活（1）。非裔美国人（AA）妇女受到了不成比例的影响； aa女人更多可能发展出侵略性的三阴性亚型，并患有复发或转移性疾病（2-4），并且与所有其他种族/种族组相比，AA乳腺癌患者的死亡率仍然最高（2- 5）。这些差异的生物学和非生物因素是复杂的，并且在很大程度上未知。同性载荷（AL）是继发压力的生理失调的有效度量，通常被使用量化乳腺癌的生理负担（10-13）。 Al已被证明是正相关的 AA妇女的乳腺癌风险和更具侵略性的表型，但在白人妇女中没有（10,12-14）。这些发现支持了社会和生物学因素有助于乳腺癌的观念特征和生存。线粒体DNA（mtDNA）异常，包括突变，缺失和副本数量变化，是癌症中经常发生的事件。最近的PAN-CACTER研究发现AA患者的肿瘤与线粒体相比，与白色相同的癌症富含线粒体的氧气并包含更多的线粒体美国人（15）。乳腺癌患者血液中的线粒体DNA（mtDNA）拷贝数增加最近被证明与Al呈正相关，表明mtDNA含量是可能的介体连接较高的Al和侵袭性乳腺肿瘤特征（10）。 mtDNA在表观遗传上通过胞嘧啶和腺嘌呤甲基化，这代表了环境调节的强大机制线粒体功能（图1，16-19）。虽然全基因组DNA甲基化的变化已与乳腺肿瘤特征，mtDNA甲基化在乳腺癌发病率/死亡率中的作用仍然存在未探索。这里提出的研究旨在更好地了解为什么黑人妇女受到更严重的乳腺癌亚型的影响不成比例的，更高死亡率。提出了流行病学，分子和替代方法来检查慢性应激对线粒体生物学的影响会导致乳腺癌差异。首先，我们会的研究AL对AA和白人患者的乳腺肿瘤组织中线粒体生物学的影响。我们将确定Al与线粒体异常相关的程度，包括mtDNA 突变/缺失，拷贝数，表观遗传修饰和线粒体酶缺陷。第二，我们会的评估应激激素对乳腺癌和正常细胞面板中线粒体功能的影响在2二维中培养的线。压力引起的mtDNA含量的变化，表观遗传修饰和代谢变化将被量化。这些方法将探索社会心理风险之间的相互作用 AA乳腺癌发病率和严重程度的因素和生物途径妇女，目的是更好地告知患者分层和治疗策略。