HMGB1 released by autophagic cancer‐associated fibroblasts maintains the stemness of luminal breast cancer cells

Cancer stem/initiating cells (CSCs/CICs) and their microenvironmental niche play a vital role in malignant tumour recurrence and metastasis. Cancer associated fibroblasts (CAFs) are major components of the niche of breast cancer initiating cells (BCICs) and their interactions may profoundly affect breast cancer progression. Autophagy has been considered as a critical process for CIC maintenance, but whether it is involved in the cross-talk between CAFs and CICs to affect tumourigenesis and pathological significance remains elusive. In this study, we found that the presence of CAFs containing high levels of LC3II, a maker of autophagosomes, was associated with more aggressive luminal human breast cancer. CAFs in human luminal breast cancer tissues with high autophagy activity enriched BCICs with increased tumourigenicity. Mechanistically, autophagic CAFs released high-mobility group box 1 (HMGB1) that activated its receptor TLR4 expressed by luminal breast cancer cells to enhance their stemness and tumourigenicity. Furthermore, immunohistochemistry of 180 luminal breast cancers revealed that high LC3II/TLR4 levels predicted an increased relapse rate and poorer prognosis. Our findings demonstrate that autophagic CAFs play a critical role in promoting the progression of luminal breast cancer through a HMGB1/TLR4 axis, and both autophagy in CAFs and TLR4 on breast cancer cells constitute potential therapeutic targets.