NDLI: Neuropilin-1 is over-expressed in claudin-low breast cancer and promotes tumor progression through acquisition of stem cell characteristics and RAS/MAPK pathway activation

Content Provider	Springer Nature : BioMed Central
Author	Tang, Yu Hin Rockstroh, Anja Sokolowski, Kamil A. Lynam, Layla-Rose Lehman, Melanie Thompson, Erik W. Gregory, Philip A. Nelson, Colleen C. Volpert, Marianna Hollier, Brett G.
Abstract	Background Triple-negative breast cancers (TNBC) have a relatively poor prognosis and responses to targeted therapies. Between 25 and 39% of TNBCs are claudin-low, a poorly differentiated subtype enriched for mesenchymal, stem cell and mitogen-activated signaling pathways. We investigated the role of the cell-surface co-receptor NRP1 in the biology of claudin-low TNBC. Methods The clinical prognostic value of NRP1 was determined by Kaplan–Meier analysis. GSVA analysis of METABRIC and Oslo2 transcriptomics datasets was used to correlate NRP1 expression with claudin-low gene signature scores. NRP1 siRNA knockdown was performed in MDA-MB-231, BT-549, SUM159 and Hs578T claudin-low cells and proliferation and viability measured by live cell imaging and DNA quantification. In SUM159 orthotopic xenograft models using NSG mice, NRP1 was suppressed by shRNA knockdown or systemic treatment with the NRP1-targeted monoclonal antibody Vesencumab. NRP1-mediated signaling pathways were interrogated by protein array and Western blotting. Results High NRP1 expression was associated with shorter relapse- and metastasis-free survival specifically in ER-negative BrCa cohorts. NRP1 was over-expressed specifically in claudin-low clinical samples and cell lines, and NRP1 knockdown reduced proliferation of claudin-low cells and prolonged survival in a claudin-low orthotopic xenograft model. NRP1 inhibition suppressed expression of the mesenchymal and stem cell markers ZEB1 and ITGA6, respectively, compromised spheroid-initiating capacity and exerted potent anti-tumor effects on claudin-low orthotopic xenografts (12.8-fold reduction in endpoint tumor volume). NRP1 was required to maintain maximal RAS/MAPK signaling via EGFR and PDGFR, a hallmark of claudin-low tumors. Conclusions These data implicate NRP1 in the aggressive phenotype of claudin-low breast cancer and offer a novel targeted therapeutic approach to this poor prognosis subtype.
Related Links	https://breast-cancer-research.biomedcentral.com/counter/pdf/10.1186/s13058-022-01501-7.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s13058-022-01501-7
Journal	Breast Cancer Research
Issue Number	1
Volume Number	24
Language	English
Publisher	BioMed Central
Publisher Date	2022-01-25
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Surgical Oncology Neuropilin Breast cancer Claudin-low Triple-negative breast cancer Cancer stem cells
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7.1/2023

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