Identification of ribosomal protein eL21 as a novel externalized protein and a target in triple-negative breast cancer.

Proteins normally localized in the intracellular compartments of healthy cells have been observed at the surface of cancer cells, despite lacking a transmembrane domain or secretion signals. This unexpected localization likely reflects yet-unknown functions and presents a unique opportunity to develop cancer cell-specific antibody- or peptide-based therapeutic strategies. While ribosomal proteins (RPs) are primarily involved in translation, several display moonlighting functions in the cytoplasm and nucleus. In this study, we uncover an extracellular form of the ribosomal protein L21 (eL21) in triple-negative breast cancer (TNBC) cells. Using complementary approaches and a broad set of antibodies, we demonstrate that eL21 localizes to the surface of cancer cells. Remarkably, we show that anti-eL21 antibodies trigger a potent, rapid and dose-dependent anti-proliferative effect, including TNBC cell cycle arrest and apoptosis. These findings identify eL21 as a novel ribosomal protein with extra-ribosomal functions at the cancer cell surface and highlight its potential as a therapeutic target in TNBC.