Ribosomal Proteins in Blood Exosomes as Markers of an Unfavorable Prognosis in Patients with Breast Cancer

Exosomes, extracellular vesicles (EVs) 30-150 nm in diameter, are known to mediate intercellular communication by transferring bioactive molecules that can reprogram recipient cell phenotypes. Our analysis of 5-year survival data from breast cancer patients (BCPs) revealed that the poorest outcomes were exclusively associated with conserved signature of three ribosomal proteins (RPs) - MRPL52, RPL28, and RPL40 (UBA52) - that were completely absent in healthy females (HFs) and better-prognosis cases. Strikingly, all patients with this exosomal RP profile succumbed to metastatic relapse within the observation period.

While RPs are known components of tumor-derived exosomes, their absence in EVs from normal cells suggests cancer-specific sorting mechanisms. To investigate this, we characterized exosomal RP cargo from three breast cancer cell lines (MCF-7, BT-474, BT-549), finding cell-type-specific RP patterns that differed from the clinical BC signature. Transfection of BT-549 cells with FLAG-tagged RPS3 (an aggressive cancer-associated RP) induced dramatic changes in exosomal RP composition, including the appearance of RPL28 - matching our clinical findings.

Bioinformatic analysis revealed that the RPs identified in BCP blood exosomes (MRPL52, RPL28, RPL40, RPS6) are associated with poor prognosis across multiple cancers and participate in key oncogenic pathways.

The concordance between our clinical and experimental data suggests that: (a) specific RPs are selectively packaged into exosomes under stress conditions; (b) this process may contribute to BC aggressiveness; (c) exosomal RP profiling could serve as a novel prognostic approach. These findings illuminate previously unrecognized roles of ribosomal components in cancer progression through EV-mediated communication.