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

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%，死亡人数超过4万人 独自生活在2020年(1)。非裔美国人(AA)女性受到的影响不成比例；AA女性受影响更大 可能发展为侵袭性三阴性亚型，并遭受复发或转移性疾病(2-4)，以及 AA乳腺癌患者的死亡率仍然高于所有其他种族/民族(2- 5)。造成这些差异的生物和非生物因素是复杂的，而且在很大程度上是未知的。 恒定负荷(AL)是继发于应激的一种有效的生理失调措施，常被使用 量化乳腺癌的生理负担(10-13)。铝已经被证明是正相关的 AA女性中乳腺癌风险和更具侵略性的表型，但在白人女性中不是 (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。 特征和生存。线粒体DNA异常，包括突变、缺失和复制 数字变化，是癌症中经常发生的事件。最近的一项泛癌症研究发现，再生障碍性贫血患者的肿瘤 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拷贝数的增加 最近发现线粒体DNA含量与AL呈正相关，提示线粒体DNA含量可能是一种调节因素 将较高的AL和侵袭性乳腺肿瘤特征联系起来(10)。线粒体DNA由表观遗传修饰 胞嘧啶和腺嘌呤甲基化，这代表了一种强大的环境调节机制 线粒体功能(图1，16-19)。虽然全基因组DNA甲基化的变化与 乳腺肿瘤的特点，线粒体DNA甲基化在乳腺癌发病率/死亡率中的作用仍然存在 未被开发的。这里提出的研究旨在更好地理解其中的社会和生物学基础 黑人女性受更严重的乳腺癌亚型和更高的影响不成比例 死亡率。提出了流行病学、分子和代谢组学的方法来检查 慢性应激对线粒体生物学的影响，因为它们促成了乳腺癌的差异。首先，我们将 研究AL对再障患者和白人患者乳腺肿瘤组织线粒体生物学的影响。 我们将确定AL与包括mtDNA在内的线粒体异常的关联程度 突变/缺失、拷贝数、表观遗传修饰和线粒体酶缺陷。第二，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 培养成2-和3-维的细胞系。应激诱导线粒体DNA含量的变化，表观遗传修饰和 新陈代谢的变化将被量化。这些方法将探索心理社会风险之间的相互作用 再生障碍性贫血患者乳腺癌发病率和严重程度差异的因素和生物学途径 妇女，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.