Rab13 Activates IL-6/STAT3 Pathway for Maintaining Stemness of Breast Tumors

Breast cancer remains a significant global health concern, characterized by its heterogeneity. Cancer stem cells (CSCs) contribute to tumor heterogeneity, drug resistance, and ultimately, cancer recurrence. The IL‑6/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway is critical for maintaining the breast cancer stem cells (BCSCs) stemness; however, the upstream regulatory mechanisms remain unclear. Here, we report that Rab13, a member of the Rab GTPase family, regulates IL‑6/STAT3 signaling to sustain the BCSCs phenotype. In HCC1806 and MDA‑MB‑231 breast cancer cells, Rab13 knockdown reduced membrane localization of IL-6 receptor (IL-6Rα), impaired IL‑6‑induced STAT3 phosphorylation, and reduced the proportions of CD44+CD24−/low and ALDH+ BCSCs populations. Rab13 depletion also inhibited tumorsphere formation, soft agar colony formation, cell migration, cell invasion, and epithelial‑mesenchymal transition (EMT). Mechanistically, Rab13 interacts with IL‑6Rα and mediates its membrane trafficking, thereby ensuring efficient IL‑6/STAT3 signaling. Activation of STAT3 by ML115 rescued the BCSCs stemness and EMT defects caused by Rab13 knockdown. These findings reveal that Rab13 maintains BCSCs stemness and promotes tumor progression via the IL‑6/STAT3‑EMT axis, suggesting Rab13 as a potential therapeutic target for breast cancer.