中樞神經系統轉移是最常見的腦惡性腫瘤，通常源自於乳腺癌（15%–25%），特別是三陰性乳腺癌患者，由於缺乏有效治療方法，因此導致患者存活率較低。目前，針對中樞神經系統轉移的診斷、預後方法和治療策略是一個迫切的臨床問題。在這項研究中，我們將研究中樞神經系統轉移的分子機制，並開發中樞神經系統轉移的三陰性乳腺癌患者開發新的診斷和治療策略。微小核糖核酸陣列分析確定miR-211在腦轉移細胞顯著高表達。高表達之miR-211於三陰性乳腺癌細胞能夠促進早期且專一性之腦轉移於疾病小鼠模型中。高表達之miR-211於三陰性乳腺癌細胞促進細胞穿透血腦屏障遷移之能力，血腦屏障附著和癌幹細胞之特性。此外，我們也證明NGN2和SOX11作為miR-211的下游調控蛋白並受miR-211專一性的調控。最重要的是，高表達之miR-211與乳腺癌或三陰性乳腺癌患者的腫瘤復發顯著相關。通過蛋白質體學分析，結果顯示軟腦膜轉移之三陰性乳腺癌細胞中ICAM2的表達顯著增加。高表達之ICAM2於三陰性乳腺癌細胞促進了早期且專一之軟腦膜轉移且造成存活率顯著降低於疾病小鼠模型中。高表達之ICAM2於三陰性乳腺癌細胞促進了細胞血腦脊液屏障粘附之能力、通過血腦脊液屏障遷移及癌幹細胞之能力。此外，pull down和抗體中和實驗闡明，ICAM2通過與脈絡叢上皮細胞中的ICAM1相互作用來促進的特異性的軟腦膜轉移。利用中和性抗體中和三陰性乳腺癌細胞中之ICAM2顯示出抑制軟腦膜轉移進展和延長小鼠存活的時間。這表明，針對ICAM2可能是治療三陰性乳腺癌軟腦膜轉移的潛在策略。綜上所述，我們的發現miR-211可能是乳腺癌或三陰性乳腺癌患者腦轉移的潛在診斷或預後標誌。此外，針對標靶ICAM2可能為治療三陰性乳腺癌軟腦膜轉移提供了一條新的治療途徑。

Brain metastases originating from the central nervous system (CNS) are commonly associated with triple-negative breast cancer (TNBC), resulting in poor patient survival due to limited treatment options. Our study focuses on understanding the molecular basis of CNS metastasis in TNBC and developing new strategies for diagnosis and treatment. We identified an elevated presence of miR-211 in brain metastatic cells through microRNA array analysis. Our findings suggest that high levels of miR-211 play a role in the early and specific colonization of the brain in vivo. Additionally, heightened miR-211 levels promote migration across the blood-brain barrier (BBB), enhance BBB adherence, and contribute to stemness properties in TNBC. Furthermore, we identified NGN2 and SOX11 as downstream targets specifically regulated by miR-211. Notably, elevated miR-211 levels in primary tumor correlated with tumor recurrence in BC or TNBC patients with brain metastasis. Moreover, our proteomic analysis unveiled increased expression of ICAM2 in leptomeningeal metastatic TNBC cells. ICAM2 was found to facilitate spinal cord colonization, leading to decreased survival rates in vivo. Our study indicates that elevated ICAM2 levels promote adhesion to the blood-cerebrospinal fluid barrier (BCB), facilitate migration across this barrier, and enhance the stemness abilities of cancer cells, all critical factors in leptomeningeal metastasis (LM) development. The interaction between ICAM2 and ICAM1 in choroid plexus epithelial cells appears pivotal in determining the specificity of LM. Targeting ICAM2, as suggested by pulldown and antibody neutralizing assays, demonstrated a potential to impede LM progression and extend survival in experimental models. This highlights the promising therapeutic potential of targeting ICAM2 in managing LM in TNBC. Our findings propose that miR-211 could serve as a promising diagnostic or prognostic marker for brain metastasis in BC or TNBC patients. Additionally, targeting ICAM2 presents a potential therapeutic strategy for addressing leptomeningeal metastasis in TNBC.

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