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Nephronectin is Correlated with Poor Prognosis in Breast Cancer and Promotes Metastasis via its Integrin-Binding Motifs

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posted on 2023-05-12, 02:50 authored by Tonje S Steigedal, Jimita Toraskar, Richard RedversRichard Redvers, Marit Valla, Synnøve N Magnussen, Anna M Bofin, Signe Opdahl, Steinar Lundgren, Bedrich EckhardtBedrich Eckhardt, John M Lamar, Judy Doherty, Richard O Hynes, Robin AndersonRobin Anderson, Gunbjørg Svineng

Most cancer patients with solid tumors who succumb to their illness die of metastatic disease. While early detection and improved treatment have led to reduced mortality, even for those with metastatic cancer, some patients still respond poorly to treatment. Understanding the mechanisms of metastasis is important to improve prognostication, to stratify patients for treatment, and to identify new targets for therapy. We have shown previously that expression of nephronectin (NPNT) is correlated with metastatic propensity in breast cancer cell lines. In the present study, we provide a comprehensive analysis of the expression pattern and distribution of NPNT in breast cancer tissue from 842 patients by immunohistochemical staining of tissue microarrays from a historic cohort. Several patterns of NPNT staining were observed. An association between granular cytoplasmic staining (in <10% of tumor cells) and poor prognosis was found. We suggest that granular cytoplasmic staining may represent NPNT-positive exosomes. We found that NPNT promotes adhesion and anchorage-independent growth via its integrin-binding and enhancer motifs and that enforced expression in breast tumor cells promotes their colonization of the lungs. We propose that NPNT may be a novel prognostic marker in a subgroup of breast cancer patients.


The mouse cell lines 67NR, 168FARN, 66cl4, 4TO7, and 4T1 were kindly provided by Dr. Fred Miller. We thank Dr. Naoko Morimura the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (NTNU) [grant numbers 46056732, 46055600, and 46077600], the Cancer Fund at St. Olav's Hospital in Trondheim, The Northern Norway Regional Health Authority (Helse Nord RHF), UiT-The Arctic University of Norway [grant number SFP1232-15], and The National Cancer Institute at NIH. We acknowledge fellowships from the National Breast Cancer Foundation of Australia to Richard Redvers and Robin Anderson. The Research Council of Norway is acknowledged for the support to the Norwegian Micro- and Nano-Fabrication Facility, NorFab [grant number 245963/F50].


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© 2018 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (

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