DEC1 Deficiency Attenuates Breast Cancer‐Induced Osteolytic Destruction by Suppression of Cancer‐Associated Fibroblast Differentiation

ABSTRACT Background Cancer‐associated fibroblasts (CAFs) in the bone microenvironment play a key role in breast cancer (BC) osteolytic bone metastases. Differentiated embryo‐chondrocyte expressed gene 1 (DEC1) has been implicated as a potential therapeutic target in CAFs. Here, we investigate the role of DEC1 within the bone microenvironment during BC cell‐induced bone destruction. Methods In vivo, a BC bone metastasis mouse model by intratibially injecting 4 T1 cells into DEC1 +/+ and DEC1 −/− mice was used to explore the effects of DEC1 deficiency in the bone microenvironment on BC osteolytic bone destruction. Bone mesenchymal stromal cells (BMSCs) isolated from DEC1 +/+ and DEC1 −/− mice were induced to differentiate into CAFs, as in vitro model to explore the roles and underlying mechanisms. Results DEC1 deficiency markedly attenuated BC‐induced osteolytic destruction. Notably, DEC1 +/+ ‐4 T1 mice exhibited a higher abundance of CAF biomarker‐positive cells in the bone microenvironment compared to DEC1 −/− ‐4 T1 mice. Mechanistically, tumor‐conditioned medium (TCM) and IL‐6 were found to promote the differentiation of BMSCs into CAFs through activation of the JAK2/STAT3 pathway, whereas DEC1 deletion suppressed this process by inhibiting JAK2/STAT3 signaling. Furthermore, DEC1 deficiency reduced RANKL secretion, thereby limiting osteoclastogenesis, and decreased PAI‐1 levels, which contributed to remodeling of the tumor microenvironment and suppression of BC cell migration. Conclusion Our findings demonstrate that DEC1 deficiency in the bone microenvironment critically restrains BC cell‐induced bone destruction through inhibition of CAF differentiation.