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

摘要 乳腺癌存活率的种族差异在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)女性。然而，最新的统计数据表明，在再生障碍性贫血妇女中，超过50%的肿瘤是雌激素 受体阳性(ER+)。ER+肿瘤被认为侵袭性较小，通常可以有效地使用 针对雌激素受体活性(如他莫昔芬)或雌激素产生(如芳香酶抑制剂)的内分泌治疗。 尽管患有ER+乳腺癌的女性总体预后良好，但AA女性仍有更大的风险 而不是死于ER+病的白人女性。我们发现芝加哥地区的AA女性有4到 死于ER+乳腺癌的风险是白人女性的5倍，即使在控制了 诊断、治疗和其他已知的预后因素。这一发现表明，生物机制是 AA女性ER+乳腺癌中的激活，导致内分泌治疗抵抗和更大的风险 故态复萌和死亡。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。这项提案的目标是调查 角鲨烯环氧酶(SQLE)是生物合成甾醇、胆固醇和氧化甾醇的关键酶。 患有ER+肿瘤的AA妇女预后不良的潜在驱动因素。我们假设ER+中的SqLE升高 AA妇女的肿瘤导致生物活性类固醇的积聚，这些类固醇具有促进肿瘤细胞的功能 扩散和生存。从机制上讲，我们希望这些甾醇通过改变内质网活动和减少 对内分泌治疗的反应性。为了研究这一点，我们提出了三个目标：1)通过以下方式定义机制 哪个Sqle在AA女性ER+乳腺肿瘤中表达上调；2)鉴定哪些Sqle调节的甾醇 与ER+乳腺肿瘤的种族相关，以及3)评估细胞功能和治疗潜力 再生障碍性贫血患者ER+肿瘤中的Sqle。为了实现这些目标，我们将利用新产生的肿瘤标本 和来自AA女性的新的临床前模型，以及我们开发的一种创新方法，以检测和 分析多种类固醇。总体而言，我们希望将Sqle确立为种族差距的关键参与者 观察ER阳性乳腺癌患者的生存情况。重要的是，我们希望发现两种新的机制 这可能解释了1)Sqle是如何导致早期复发的，以及2)为什么Sqle在ER+中表达升高 再障妇女的肿瘤。归根结底，这项工作有可能通过改善患者的存活率来增加健康公平 AA患有ER+乳腺癌的妇女通过开发新的预防和治疗策略 针对导致不同结果的潜在分子机制。

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.