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

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.