Open Access Highly Accessed Research article

Lipocalin 2 expression is associated with aggressive features of endometrial cancer

Monica Mannelqvist12, Ingunn M Stefansson12, Elisabeth Wik34, Kanthida Kusonmano5, Maria B Raeder34, Anne M Øyan16, Karl-Henning Kalland16, Marsha A Moses78, Helga B Salvesen34 and Lars A Akslen12*

Author Affiliations

1 The Gade Institute, Section for Pathology, University of Bergen, Bergen, Norway

2 Department of Pathology, Haukeland University Hospital, Bergen, Norway

3 Department of Clinical Medicine, University of Bergen, Bergen, Norway

4 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway

5 Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway

6 Department of Microbiology, Haukeland University Hospital, Bergen, Norway

7 Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

8 Department of Surgery, Harvard Medical School, Boston, MA, USA

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BMC Cancer 2012, 12:169  doi:10.1186/1471-2407-12-169

Published: 6 May 2012

Abstract

Background

Increased expression of lipocalin 2 (LCN2) has been observed in several cancers. The aim of the present study was to investigate LCN2 in endometrial cancer in relation to clinico-pathologic phenotype, angiogenesis, markers of epithelial-mesenchymal transition (EMT), and patient survival.

Methods

Immunohistochemical staining was performed using a human LCN2 antibody on a population-based series of endometrial cancer patients collected in Hordaland County (Norway) during 1981-1990 (n = 256). Patients were followed from the time of primary surgery until death or last follow-up in 2007. The median follow-up time for survivors was 17 years. Gene expression data from a prospectively collected endometrial cancer series (n = 76) and a publicly available endometrial cancer series (n = 111) was used for gene correlation studies.

Results

Expression of LCN2 protein, found in 49% of the cases, was associated with non-endometrioid histologic type (p = 0.001), nuclear grade 3 (p = 0.001), >50% solid tumor growth (p = 0.001), ER and PR negativity (p = 0.028 and 0.006), and positive EZH2 expression (p < 0.001). LCN2 expression was significantly associated with expression of VEGF-A (p = 0.021), although not with other angiogenesis markers examined (vascular proliferation index, glomeruloid microvascular proliferation, VEGF-C, VEGF-D or bFGF2 expression). Further, LCN2 was not associated with several EMT-related markers (E-cadherin, N-cadherin, P-cadherin, β-catenin), nor with vascular invasion (tumor cells invading lymphatic or blood vessels). Notably, LCN2 was significantly associated with distant tumor recurrences, as well as with the S100A family of metastasis related genes. Patients with tumors showing no LCN2 expression had the best outcome with 81% 5-year survival, compared to 73% for intermediate and 38% for the small subgroup with strong LCN2 staining (p = 0.007). In multivariate analysis, LCN2 expression was an independent prognostic factor in addition to histologic grade and FIGO stage.

Conclusion

Increased LCN2 expression is associated with aggressive features and poor prognosis in endometrial cancer.