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

项目总结/摘要PI：休克，丽莎S。 据估计，乳腺癌占女性所有新诊断癌症的30%， 仅在2020年（1）。非裔美国人（AA）妇女受到不成比例的影响; AA妇女更多 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），以及 AA乳腺癌患者的死亡率与所有其他种族/民族组相比仍然最高（2- 5）。造成这些差异的生物和非生物因素很复杂，而且基本上不为人所知。 非稳态负荷（AL）是继发于应激的生理失调的有效测量方法， 以量化乳腺癌的生理负担（10-13）。AL已被证明是正相关的 在AA女性中有乳腺癌的风险和更具侵略性的表型，但在白色女性中没有 (10，12 -14）。这些发现支持了社会和生物因素导致乳腺癌的观点 特色与生存线粒体DNA（mtDNA）异常，包括突变、缺失和拷贝 数量变化是癌症中常见的事件。最近的一项泛癌症研究发现，AA患者的肿瘤 富含线粒体OXPHOS，并且比来自白色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 最近显示与AL呈正相关，提示mtDNA含量可能是一种介导因素 将较高的AL与侵袭性乳腺肿瘤特征联系起来（10）。MtDNA通过以下方式进行表观遗传修饰： 胞嘧啶和腺嘌呤甲基化，这是一个强大的机制，环境调节 线粒体功能（图1，16-19）。虽然全基因组DNA甲基化变化与 乳腺肿瘤的特点，mtDNA甲基化在乳腺癌发病率/死亡率中的作用仍然存在 未开发的这里提出的研究旨在更好地理解为什么会这样的社会和生物学基础 黑人妇女不成比例地受到更严重的乳腺癌亚型的影响， 死亡率。流行病学，分子和代谢组学的方法，提出了检查 慢性压力对线粒体生物学的影响，因为它们有助于乳腺癌的差异。一是 研究AL对AA和白色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。二是 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 二维和三维培养的细胞系。应激诱导的线粒体DNA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患者乳腺癌发病率和严重程度差异的潜在因素和生物学途径 女性，目的是更好地告知患者分层和治疗策略。

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.