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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。