Chemoresistance is a multifactorial and complex phenomenon, leading to re-adjustment of several intracellular signaling pathways and expression pattern which compromises the efficacy of cancer drug chemo-therapy. Via comparative analysis of sensitive and doxorubicin-resistant 4T1 cells, here we show that Lipocalin 2 (LCN2) is downregulated at the mRNA and protein level in resistant cells. The pro-inflammatory cytokine, IL-1β was found to be a potent inducer of LCN2 expression most likely involving STAT3 activation. Upregulation in both sensitive and resistant 4T1 cells argues against complete silencing of the LCN2 gene. Coinciding with LCN2 downregulation, we observed an increased activation of bone morphogenetic protein (BMP)-signaling in resistant cells, as evidenced by higher Smad1/5/9 phosphorylation and Id1 target gene expression. Blockade of the BMP-pathway by Dorsomorphin increased the expression of LCN2. Conversely, BMP2, which is known to be a pro-tumorigenic ligand in breast cancer, potently inhibited LCN2 expression at both the mRNA and protein level in resistant cells. These findings indicate that in doxorubicin-resistant 4T1 cells, LCN2 expression is negatively regulated by BMP signaling.

化疗耐药是一种多因素和复杂的现象，会导致多种细胞内信号通路和表达模式的重新调整，从而影响抗癌药物化疗的疗效。通过对敏感和多柔比星抗性 4T1 细胞的比较分析，我们发现脂质运载蛋白 2 (LCN2) 在抗性细胞中的 mRNA 和蛋白质水平被下调。发现促炎细胞因子 IL-1β 是 LCN2 表达的有效诱导剂，很可能与 STAT3 激活有关。敏感和抗性 4T1 细胞的上调反对 LCN2 基因的完全沉默。与 LCN2 下调一致，我们观察到抗性细胞中骨形态发生蛋白 (BMP) 信号的激活增加，如更高的 Smad1/5/9 磷酸化和 Id1 靶基因表达所证明的那样。Dorsomorphin 对 BMP 通路的阻断增加了 LCN2 的表达。相反，已知是乳腺癌促肿瘤发生配体的 BMP2 在耐药细胞的 mRNA 和蛋白质水平上有效抑制 LCN2 表达。这些发现表明，在耐多柔比星的 4T1 细胞中，LCN2 的表达受到 BMP 信号的负调控。