PO.CL05.09 · 临床研究
探究糖皮质激素诱导亮氨酸拉链蛋白(GILZ)在三阴性乳腺癌中的作用
Investigating the role of glucocorticoid-induced leucine zipper (GILZ) in triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌是美国女性的主要死亡原因之一，据估计每8名女性中就有1人会在一生中罹患该疾病。缺乏激素受体(雌激素/孕激素)和HER2受体表达的乳腺癌被称为三阴性乳腺癌(TNBC)。TNBC约占美国女性所有乳腺癌病例的15-20%，通常以复杂的肿瘤微环境为特征，常表现出炎症加剧和免疫抑制。这使得TNBC对许多治疗产生耐药，导致其五年总生存率低于其他乳腺癌亚型。我们实验室的证据表明，TSC22D3基因与TNBC患者更长的生存期相关。TSC22D3编码免疫调节蛋白糖皮质激素诱导亮氨酸拉链蛋白(GILZ)。GILZ的表达由糖皮质激素与细胞核内激素反应元件结合而诱导，被认为是GR激活后最早合成的转录本之一。已知GILZ通过阻止诸如丝裂原活化蛋白激酶(MAPKs)等酶以及大鼠肉瘤蛋白(Ras)和缺氧诱导因子1α(HIF1a)等蛋白的下游磷酸化或激活事件，直接抑制炎症和细胞增殖，从而抑制炎症信号传导。虽然GILZ蛋白的功能和作用此前已在包括肾脏系统、中枢神经系统和消化系统在内的许多系统中得到研究，但其在乳腺癌研究中的表达和作用尚未得到明确观察。此外，GILZ抑制炎症的机制随氧供情况而变化，其背后的生物学原因也仍不清楚。本项目的目标是：1)确定一种可调节GILZ表达的潜在化合物，以便更好地在体外观察其活性；2)探究在TNBC细胞不同氧供状态下影响GILZ作用的关键蛋白-蛋白相互作用。本研究旨在通过考察可降低或过表达GILZ蛋白水平的现有化合物，并检查不同环境下潜在的偏向性蛋白结合，来探索和阐明GILZ在可适应性肿瘤微环境中的特异性免疫调节作用。总而言之，表征GILZ在不同条件下的活性和作用，有望为三阴性乳腺癌等炎症驱动性疾病的靶向治疗开发提供方向。
查看英文原文 English abstract
Breast cancer is one of the leading causes of death for American women, with 1 in 8 expected to develop the disease in their lifetime. Breast cancers that lack the expression of hormone receptors (estrogen/progesterone) and the HER2 receptor are known as triple negative breast cancer (TNBC). TNBC accounts for about 15-20% of all breast cancer cases in American women, and is commonly characterized by a complex tumor microenvironment that often exhibits increased inflammation and immune suppression. This makes TNBC resistant to many treatments, resulting in an overall lower five-year survival rate than other breast cancer subtypes.Evidence found in our lab demonstrates that the gene TSC22D3 is correlated with longer survival in patients with TNBC. TSC22D3 encodes the immunomodulatory protein Glucocorticoid-Induced Leucine Zipper (GILZ). GILZ expression is induced by glucocorticoid binding to hormone response elements in the nucleus and is thought to be one of the first transcripts synthesized after GR activation. GILZ is known to directly inhibit inflammation and cell proliferation by preventing downstream phosphorylation or activation events of enzymes such as mitogen-activated protein kinases (MAPKs), and proteins like rat sarcoma protein (Ras) and hypoxia inducible factor 1 alpha (HIF1a) to suppress inflammatory signaling.While the function and effects of the GILZ protein have been previously studied in many systems including the renal system, central nervous system and digestive system, its expression and effects have not been explicitly observed in breast cancer studies. Furthermore, the mechanism by which GILZ inhibits inflammation is variable with oxygen availability and the biological reason for this also remains unknown. The goal of this project is to 1) identify a potential chemical compound to modulate GILZ expression to better observe the activity in vitro and, 2) investigate key protein-protein interactions that influence GILZ action in variable oxygen availability states in TNBC cells. This work seeks to explore and clarify the specific immunomodulatory effects of GILZ in adaptable tumor microenvironments by investigating existing compounds that can reduce or overexpress GILZ protein levels and examining potential biased protein binding across different environments. All told, characterizing the activity and role of GILZ in varying conditions will potentially lead to the development of targeted therapeutic treatment for inflammation-driven diseases such as triple negative breast cancer.
利益披露 Disclosure
D. A. Hill, None.