The brain is often reported as the first site of recurrence among breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Although most HER2+tumors metastasize to the subcortical region of the brain, a subset develops in the cortical region. We hypothesize that factors in cerebrospinal fluid (CSF) play a critical role in the adaptation, proliferation, and establishment of cortical metastases. We established novel cell lines using patient biopsies to model breast cancer cortical and subcortical metastases. We assessed the localization and growth of these cells in vivo and proliferation and apoptosis in vitro under various conditions. Proteomic analysis of human CSF identified astrocyte-derived factors that support the proliferation of cortical metastases, and we used neutralizing antibodies to test the effects of inhibiting these factors both in vivo and in vitro. The cortical breast cancer brain metastatic cells exhibited greater proliferation than subcortical breast cancer brain metastatic cells in CSF containing several growth factors that nourish both the CNS and tumor cells. Specifically, the astrocytic paracrine factors IGFBP2 and CHI3LI promoted the proliferation of cortical metastatic cells and the formation of metastatic lesions. Disruption of these factors suppressed astrocyte-tumor cell interactions in vitro and the growth of cortical tumors in vivo. Our findings suggest that inhibition of IGFBP2 and CHI3LI signaling, in addition to existing treatment modalities, may be an effective therapeutic strategy targeting breast cancer cortical metastasis.

中文翻译：

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脑脊液中的星形细胞IGFBP2和CHI3L1驱动HER2 +乳腺癌的皮质转移。

人们经常报告大脑是过度表达人类表皮生长因子受体2（HER2）的乳腺癌患者中的第一个复发部位。尽管大多数HER2 +肿瘤转移到大脑的皮层下区域，但在皮层区域会发育一个亚群。我们假设，脑脊液（CSF）中的因素在皮层转移的适应，增殖和建立中起关键作用。我们建立了使用患者活检模型乳腺癌皮层和皮层下转移的新型细胞系。我们评估了这些细胞在各种条件下的体内定位和生长以及体外的增殖和凋亡。对人类CSF的蛋白质组学分析确定了星形胶质细胞衍生的因子，这些因子支持皮层转移的增殖，我们使用中和抗体在体内和体外测试了抑制这些因素的作用。皮质乳腺癌脑转移细胞的表现出比脑脊液中皮质亚乳腺癌脑转移细胞更大的增殖，其中CSF中含有几种可滋养中枢神经系统和肿瘤细胞的生长因子。具体来说，星形细胞旁分泌因子IGFBP2和CHI3LI促进了皮质转移细胞的增殖和转移性病变的形成。这些因素的破坏在体外抑制了星形胶质细胞与肿瘤细胞的相互作用，并在体内抑制了皮质肿瘤的生长。我们的发现表明，除了现有的治疗方式外，抑制IGFBP2和CHI3LI信号传导可能是针对乳腺癌皮层转移的有效治疗策略。