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

摘要 乳腺癌生存率的种族差异在很大程度上归因于晚期诊断， 与非西班牙裔白色人相比，非裔美国人（AA）中三阴性乳腺癌的发生率增加 （白色）女性。然而，最新统计表明，AA女性中超过50%的肿瘤是雌激素 受体阳性（ER+）。ER+肿瘤被认为是侵袭性较低的，并且通常用以下药物有效治疗： 靶向ER活性（即他莫昔芬）或雌激素产生（即芳香酶抑制剂）的内分泌疗法。 尽管ER+乳腺癌女性的预后一般较好，但AA女性仍有更大的风险。 比白色女性死于ER+疾病的几率要高。我们发现，在芝加哥地区的AA妇女有一个4至 5-ER+乳腺癌的死亡风险比白色女性高一倍，即使在控制了 诊断、治疗和其他已知的预后因素。这一发现意味着生物学机制是 在AA女性的ER+乳腺癌中激活，导致对内分泌治疗的抵抗和更大的风险 复发和死亡我们的首要目标是确定生物和分子机制有助于 ER+乳腺癌患者的种族生存差异。本提案的目的是调查 SQLE（角鲨烯环氧酶）是甾醇、胆固醇和氧化甾醇生物合成中的关键酶， ER+肿瘤AA女性患者预后不良的潜在驱动因素。我们假设ER+患者的SQLE升高 AA妇女的肿瘤导致生物活性甾醇的积累，其功能是促进肿瘤细胞的增殖， 增殖和生存。从机制上讲，我们预计这些固醇通过改变ER活性和降低ER活性来发挥作用。 对内分泌治疗的反应。为了研究这一点，我们提出了3个目标：1）定义的机制， 其中SQLE在AA女性的ER+乳腺肿瘤中上调; 2）鉴定SQLE调节的固醇， 与ER+乳腺肿瘤中的种族相关，和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 和新的临床前模型，以及我们开发的一种创新方法， 分析多种甾醇种类。总的来说，我们希望建立SQLE作为一个关键的球员在种族差距 在ER+乳腺癌患者的生存率中观察到。重要的是，我们希望发现两个新的机制， 这可以解释i）SQLE如何有助于早期复发和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老年人的生存率来提高健康公平性。 通过开发新的预防和治疗策略， 靶向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.