Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion

Abstract

Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC-specific targeted therapies exist. In this study we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC versus non-IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non-IBC cell lines. High expression was associated with poor-prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced colony formation, migration, and cancer stem cell populations in vitro, and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2-silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC.

Lipocalin 2 upregulation mediates the detrimental effects of therapy-induced senescence in breast cancer cells

“…Previous studies have suggested that LCN2 promotes breast cancer progression by enhancing migratory and invasive capabilities of breast cancer cells (24, 25). On account of the substantial LCN2 upregulation we detected in cells treated with senescent CM, we hypothesize that the SASP enhances aggressive breast cancer phenotypes at least in part through upregulation of LCN2.…”

Taxane chemotherapy leads to breast cancer dormancy escape by stromal injury mediated IL-6/MAP2K signaling

“…3D). The most significantly enriched genes in D2.0Rs upon docetaxel treatment were known protumor genes such as Fth1, Lcn2, Cxcl5, Tubb5, Tuba1a, Tubb4b and Hmox1 , which have been implicated in chemo-resistance (21, 26, 27), breast cancer tumorigenesis (23), invasiveness, metastatic colonization (24) and cancer cell survival (22). IPA revealed several upstream activated regulatory molecules in cancer cells including Hras, Myc, Mek , etc.…”

“…Fig. 3B shows the top 20 upregulated genes in DTX and VEH organoid datasets, wherein genes associated with autophagy induced dormancy (Col1a1, Stmn1) and tumor suppression (Tpi2, Tpm2) were enriched in VEH group (18)(19)(20), while genes associated with chemoresistance (Fth1, Hmox1), breast cancer tumorigenesis (Lcn2), cancer proliferation and invasiveness (Cxcl5, Spp1) were enriched in DTX group (21)(22)(23)(24)(25). Ingenuity pathways analysis (IPA) of pathways associated with DTX treatment enriched transcripts demonstrated activation (z-score > 1) of multiple pathways related to cancer pathogenesis, cytokine signaling, cell proliferation and anti-apoptosis, etc.…”

5-methylcytosine profile of mRNA in breast cancer brain metastasis

“…Based on our nding, m5C of MMP9 gene may take part in brain metastasis but the complete mechanism still needs to be further studied. LCN2 (Lipocalin 2), signi cantly predicts MMP9 levels in women with breast cancer [58], is involved in the epithelial-to-mesenchymal transition, angiogenesis, and cell migration and invasion in breast cancer [59].…”