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：
10527841
负责人：
Lisa Sale Shock
金额：
$ 21.77万
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/10527841
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 DNA Methylation DNA Sequence Alteration DNA copy number Defect Deletion Mutation Detection Development Disease Electronic Health Record Endocrine Enzymes Epidemiology Epigenetic Process Ethnic group Event Exposure to Glucocorticoid Receptor Glucocorticoids Goals Hormones Immune system In Vitro Incidence Individual Differences Intervention Knowledge Lead Link Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Measures Mediating Mediator of activation protein Metabolic Metastatic/Recurrent Methylation Mitochondria Mitochondrial DNA Modeling Modification Molecular Mutation Mutation Analysis Normal Cell Outcome Oxidative Phosphorylation Pathway interactions Patients Phenotype Physiological Ploidies Population Psychosocial Stress Race Recurrence Regulation Risk Factors Role Secondary to Series Severities Shock Signal Pathway Socioeconomic Status Stress System Tumor Tissue 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 screening social social factors stressor treatment strategy triple-negative invasive breast carcinoma tumor two-dimensional

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. 据估计，乳腺癌占女性所有新诊断癌症的 30%，超过 40,000 人因乳腺癌而死亡仅生活在 2020 年 (1)。非裔美国 (AA) 女性受到的影响尤为严重； AA女性比较多可能发展为侵袭性三阴性亚型，并患有复发性或转移性疾病 (2-4)，并且与所有其他种族/族裔群体相比，AA 型乳腺癌患者的死亡率仍然最高（2- 5）。这些差异背后的生物和非生物因素非常复杂，而且很大程度上是未知的。稳态负荷 (AL) 是衡量继发于压力的生理失调的有效措施，经常使用量化乳腺癌的生理负担 (10-13)。 AL 已被证明呈正相关 AA 女性有乳腺癌风险且更具侵袭性表型，但白人女性则不然 (10,12-14)。这些发现支持社会和生物因素导致乳腺癌的观点特征和生存。线粒体 DNA (mtDNA) 异常，包括突变、缺失和复制数字变化是癌症中常见的事件。最近的一项泛癌研究发现 AA 患者的肿瘤富含线粒体 OXPHOS，并且比来自白人的相同癌症含有更多的线粒体美国人 (15)。乳腺癌患者血液中线粒体 DNA (mtDNA) 拷贝数增加最近被证明与 AL 呈正相关，表明 mtDNA 含量是一个可能的介质将较高的 AL 与侵袭性乳腺肿瘤特征联系起来 (10)。 MtDNA 通过表观遗传修饰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 甲基化变化与乳腺肿瘤特征，mtDNA 甲基化在乳腺癌发病率/死亡率中的作用仍然存在未经探索。这里提出的研究旨在更好地理解其社会和生物学基础黑人女性不成比例地受到更严重的乳腺癌亚型和更高的乳腺癌亚型的影响死亡率。提出了流行病学、分子和代谢组学方法来检查慢性压力对线粒体生物学的影响，因为它们导致乳腺癌差异。首先，我们将研究 AL 对 AA 和白人患者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（包括 mtDNA）相关的程度突变/缺失、拷贝数、表观遗传修饰和线粒体酶缺陷。其次，我们将评估应激激素对一组乳腺癌和正常细胞线粒体功能的影响以 2 维和 3 维培养的细胞系。应激引起的 mtDNA 含量变化、表观遗传修饰和代谢变化将被量化。这些方法将探讨心理社会风险之间的相互作用 AA 之间乳腺癌发病率和严重程度差异的因素和生物学途径女性，目的是更好地了解患者分层和治疗策略。