Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.

中文翻译：

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ICAM-1 通过与 EGFR 的直接相互作用在驱动三阴性乳腺癌转移进展中的肿瘤内在作用


三阴性乳腺癌 （TNBC） 是最具侵袭性的亚型，由于缺乏批准的靶向治疗，因此面临严峻挑战。因此，迫切需要确定针对这种情况的有效治疗靶点。虽然表皮生长因子受体 （EGFR） 在 TNBC 中显着表达并被认为是治疗靶点，但由于其相关的副作用和有限的疗效，抗 EGFR 疗法尚未获得批准用于治疗乳腺癌。在这里，我们发现细胞间粘附分子-1 （ICAM-1） 在转移性乳腺癌中表现出表达水平升高，并作为 EGFR 激活的关键结合接头蛋白，在恶性进展中起关键作用。肿瘤表达的 ICAM-1 激活 EGFR 在 JAK1/STAT3 通路内启动偏倚信号传导，从而驱动上皮-间质转化并促进转移加剧，而不影响肿瘤生长。值得注意的是，ICAM-1 中和抗体治疗显着抑制了乳腺癌原位异种移植小鼠模型中的癌症转移。总之，我们将 ICAM-1 鉴定为 EGFR 激活的新型肿瘤内在调节因子，为 TNBC 特异性抗 EGFR 疗法的开发提供了有价值的见解。