Glycoproteomics Identifies Plexin-B3 as a Targetable Cell Surface Protein Required for the Growth and Invasion of Triple-Negative Breast Cancer Cells

Driven by the lack of targeted therapies, triple-negative
breast cancers
(TNBCs) have the worst overall survival of all breast cancer subtypes.
Considering that cell surface proteins are favorable drug targets
and are predominantly glycosylated, glycoproteome profiling has significant
potential to facilitate the identification of much-needed drug targets
for TNBCs. Here, we performed N-glycoproteomics on
six TNBCs and five normal control (NC) cell lines using hydrazide-based
enrichment. Quantitative proteomics and integrative data mining led
to the discovery of Plexin-B3 (PLXNB3), a previously undescribed TNBC-enriched
cell surface protein. Furthermore, siRNA knockdown and CRISPR-Cas9
editing of in vitro and in vivo models show that PLXNB3 is required
for TNBC cell line growth, invasion, and migration. Altogether, we
provide insights into N-glycoproteome remodeling
associated with TNBCs and functional evaluation of an extracted target,
which indicate the surface protein PLXNB3 as a potential therapeutic
target for TNBCs.