Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion.

Emilly S Villodre,Ginette Santiago‐Sanchez,Wintana Balema,François Bertucci,Bisrat G Debeb,Xiaoping Su,Pascal Finetti,Richard Larson,Kristen Gomez,Naoto T Ueno,Savitri Krishnamurthy,Juhee Song,Wendy A Woodward,Steven Van Laere,Xiaoding Hu,Shane R Stecklein,Debu Tripathy,Pablo Vivas‐Mejía

doi:10.1002/1878-0261.13074

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 vs 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.

Highlights

Inflammatory breast cancer (IBC) is the most aggressive and deadly variant of primary breast cancer
High expression of lipocalin 2 (LCN2) was associated with variables commonly associated with poor outcome: younger patients’ age, high grade, advanced stage tumors, ductal type, estrogen receptor (ER)-negative status, progesterone receptor (PR)-negative status, Erb-B2 receptor tyrosine kinase 2 (ERBB2)-positive status, and aggressive molecular subtypes [ERBB2+ and triple-negative breast cancer (TNBC) subtypes]
We found that LCN2-high tumors had significantly shorter overall survival (P < 0.0001) than LCN2-low tumors (Fig. 1A)

Summary

Introduction

Inflammatory breast cancer (IBC) is the most aggressive and deadly variant of primary breast cancer. Even with multimodality treatment strategies, survival rates for women with IBC are far lower than for those with other types of breast carcinoma (nonIBC), with estimated 5-year overall survival rates limited to 40% vs 63% for non-IBC [4,6,7,8,9]. These features underscore the critical need to better define the mechanisms that drive the aggressive behavior of IBC and to develop novel agents to improve the overall prognosis for women with IBC. Identification of specific targets and unraveling the mechanisms of growth and metastasis of this aggressive disease could lead to improvements in IBC patient survival

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Results

Conclusion