Differential regulation of Lipocalin 2 (LCN2) in doxorubicin-resistant 4T1 triple negative breast cancer cells

Chemoresistance is a multifactorial and complex phenomenon, leading to re-adjustment of several intracellular signaling pathways and expression patterns 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. •LCN2 is induced by pro-inflammatory cytokines in doxorubicin-resistant 4T1 cells.•LCN2 is downregulated in 4T1 cells that become resistant to doxorubicin.•Blunting BMP signaling in doxorubicin-sensitive 4T1 cells increases LCN2 expression.•STAT3 activation is involved in LCN2 expression.•LCN2 is one critical mediator influencing metastatic and aggressive cell behavior in chemoresistance.