In triple-negative breast cancer (TNBC), the lack of therapeutic markers and effective targeted therapies result in an incurable metastatic disease associated with a poor prognosis. Crosstalks within the tumor microenvironment (TME), including those between cancer and stromal cells, affect the tumor heterogeneity, growth, and metastasis. Previously, we have demonstrated that IL-6, IL-8, and CCL5 play a significant role in TNBC growth and metastasis. In this study, we performed a systematic analysis of cytokine factors secreted from four stromal components (fibroblasts, macrophages, lymphatic endothelial cells, and blood microvascular endothelial cells) induced by four TNBC cell types. Through bioinformatic analysis, we selected putative candidates of secreted factors from stromal cells, which are involved in EMT activity, cell proliferation, metabolism, and matrisome pathways. Among the candidates, LCN2, GM-CSF, CST3, IL-6, IL-8, and CHI3L1 are ranked highly. Significantly, Lipocalin-2 (LCN2) is upregulated in the crosstalk of stromal cells and four different TNBC cells. We validated the increase of LCN2 secreted from four stromal cells induced by TNBC cells. Using a specific LCN2 antibody, we observed the inhibition of TNBC cell growth and migration. Taken together, these results propose secreted factors as molecular targets to treat TNBC progression via crosstalk with stromal components.

在三阴性乳腺癌（TNBC）中，缺乏治疗标志物和有效的靶向治疗会导致无法治愈的转移性疾病，且预后不良。肿瘤微环境（TME）内的串扰，包括癌症和基质细胞之间的串扰，影响肿瘤的异质性、生长和转移。此前，我们已经证明 IL-6、IL-8 和 CCL5 在 TNBC 生长和转移中发挥重要作用。在本研究中，我们对四种 TNBC 细胞类型诱导的四种基质成分（成纤维细胞、巨噬细胞、淋巴内皮细胞和血液微血管内皮细胞）分泌的细胞因子进行了系统分析。通过生物信息学分析，我们选择了基质细胞分泌因子的假定候选因子，这些因子参与 EMT 活性、细胞增殖、代谢和基质体途径。在候选者中，LCN2、GM-CSF、CST3、IL-6、IL-8和CHI3L1排名靠前。值得注意的是，Lipocalin-2 (LCN2) 在基质细胞和四种不同 TNBC 细胞的串扰中上调。我们验证了 TNBC 细胞诱导的四种基质细胞分泌的 LCN2 的增加。使用特定的 LCN2 抗体，我们观察到 TNBC 细胞生长和迁移的抑制。总而言之，这些结果提出分泌因子作为分子靶标，通过与基质成分的相互作用来治疗 TNBC 进展。