SQLE and Sterols Contribute to Racial Disparity in ER+ Breast Cancer Patient Survival

SQLE 和甾醇导致 ER 乳腺癌患者生存率的种族差异

基本信息

批准号：
10571020
负责人：
Jonna Frasor
金额：
$ 23.82万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-03 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10571020
关键词：
8q24 African American Area Aromatase Inhibitors Automobile Driving Binding Biological Breast Cancer Model Breast Cancer Patient Cell Proliferation Cell Survival Cell Therapy Cell physiology Cessation of life Chicago Cholesterol Chromosomes Collection Data Development Diagnosis Disease Enzymes Epoxy Compounds Estrogen Receptors Estrogen receptor positive Estrogens Freezing Genomics Goals Incidence Mammary Neoplasms Messenger RNA Methods Molecular Normal tissue morphology Not Hispanic or Latino Organoids Outcome Patient-Focused Outcomes Patients Pre-Clinical Model Prevention strategy Production Prognosis Prognostic Factor Race Recurrence Relapse Resistance Risk Role Squalene Stage at Diagnosis Sterol Biosynthesis Pathway Sterols Survival Rate Tamoxifen Testing Tumor Promotion Tumor Subtype Up-Regulation Woman Work breast cancer survival cancer type cohort epoxidase health equity hormone therapy improved inhibitor innovation insight mRNA Expression malignant breast neoplasm mortality risk novel outcome disparities protein expression racial disparity racial diversity relapse risk response statistics survival disparity targeted treatment therapeutic target treatment strategy triple-negative invasive breast carcinoma tumor

项目摘要

ABSTRACT The racial disparity in breast cancer survival rates has largely been attributed to late-stage diagnoses and increased incidence of triple negative breast cancer in African American (AA) compared to non-Hispanic White (white) women. However, the latest statistics indicate that more than 50% of tumors in AA women are estrogen receptor positive (ER+). ER+ tumors are considered less aggressive and are typically treated effectively with endocrine therapies that target ER activity (i.e. tamoxifen) or estrogen production (i.e. aromatase inhibitors). Despite a generally favorable prognosis for women with ER+ breast cancer, AA women still have a greater risk than white women of dying from ER+ disease. We have found that AA women in the Chicago area have a 4 to 5-fold greater risk of death from ER+ breast cancer than white women, even after controlling for stage at diagnosis, treatment, and other known prognostic factors. This finding implies that biologic mechanisms are activated in ER+ breast cancer from AA women, resulting in resistance to endocrine therapy and a greater risk of relapse and death. Our overarching goal is to identify biological and molecular mechanisms contributing to the racial survival disparity in ER+ breast cancer patients. The goal of this proposal is to investigate the role of SQLE (squalene epoxidase), a key enzyme in the biosynthesis of sterols, cholesterol, and oxysterols, as a potential driver of poor outcome in AA women with ER+ tumors. We hypothesize that elevated SQLE in ER+ tumors of AA women leads to an accumulation of biologically active sterols that function to promote tumor cell proliferation and survival. Mechanistically, we expect these sterols to function by altering ER activity and reducing responsiveness to endocrine therapies. To investigate this, we propose 3 aims: 1) to define the mechanism by which SQLE is up-regulated in ER+ breast tumors in AA women; 2) to identify SQLE-regulated sterols that are associated with race in ER+ breast tumors, and 3) to assess the cellular function and therapeutic potential of SQLE in ER+ tumors of AA women. To accomplish these aims, we will utilize newly generated tumor collections and novel preclinical models from AA women, as well as an innovative method we developed to detect and analyze multiple sterol species. Overall, we expect to establish SQLE as a critical player in the racial disparity observed in survival of patients with ER+ breast cancer. Importantly, we expect to uncover two new mechanisms that may explain i) how SQLE contributes to early relapse and ii) why SQLE expression is elevated in ER+ tumors of AA women. Ultimately, this work has the potential to increase health equity by improving survival for AA women with ER+ breast cancer through the development of novel preventive and treatment strategies that target underlying molecular mechanisms contributing to disparate outcomes.

抽象的乳腺癌生存率的种族差异很大程度上归因于晚期诊断和与非西班牙裔白人相比，非裔美国人 (AA) 三阴性乳腺癌的发病率增加（白人）妇女。然而，最新统计表明，AA女性50%以上的肿瘤是雌激素所致受体阳性（ER+）。 ER+ 肿瘤被认为侵袭性较小，通常可以通过以下方法有效治疗：针对 ER 活性（即他莫昔芬）或雌激素产生（即芳香酶抑制剂）的内分泌治疗。尽管 ER+ 乳腺癌女性的预后普遍良好，但 AA 女性的风险仍然较高死于 ER+ 疾病的白人女性多于白人女性。我们发现芝加哥地区的 AA 女性有 4 至即使在控制了 ER+ 乳腺癌分期后，ER+ 乳腺癌的死亡风险比白人女性高 5 倍诊断、治疗和其他已知的预后因素。这一发现意味着生物机制是在 AA 女性的 ER+ 乳腺癌中被激活，导致对内分泌治疗的抵抗和更大的风险的复发和死亡。我们的首要目标是确定有助于 ER+乳腺癌患者的种族生存差异。该提案的目的是调查 SQLE（角鲨烯环氧化酶）是甾醇、胆固醇和氧甾醇生物合成的关键酶，作为患有 ER+ 肿瘤的 AA 女性预后不良的潜在驱动因素。我们假设 ER+ 中的 SQLE 升高 AA 女性的肿瘤会导致生物活性甾醇的积累，从而促进肿瘤细胞的生长增殖和生存。从机制上讲，我们期望这些甾醇通过改变 ER 活性并减少对内分泌治疗的反应。为了研究这个问题，我们提出了 3 个目标：1）通过以下方式定义机制： SQLE 在 AA 女性的 ER+ 乳腺肿瘤中上调； 2) 识别 SQLE 调节的甾醇与 ER+ 乳腺肿瘤的种族相关，3) 评估细胞功能和治疗潜力 AA 女性 ER+ 肿瘤中的 SQLE。为了实现这些目标，我们将利用新生成的肿瘤集合以及来自 AA 女性的新型临床前模型，以及我们开发的一种创新方法来检测和分析多种甾醇种类。总体而言，我们希望将 SQLE 打造为解决种族差异的关键角色在 ER+ 乳腺癌患者的生存中观察到。重要的是，我们期望发现两种新机制这可以解释 i) SQLE 如何导致早期复发以及 ii) 为什么 SQLE 表达在 ER+ 中升高 AA 女性的肿瘤。最终，这项工作有可能通过提高生存率来提高健康公平性通过开发新的预防和治疗策略，患有 ER+ 乳腺癌的 AA 女性针对导致不同结果的潜在分子机制。