Endogenous osteoprotegerin (OPG) represses ERα and promotes stemness and chemoresistance in breast cancer cells.

Breast cancer (BC) is the most prevalent cancer and the leading cause of death among women worldwide. The osteoprotegerin (OPG) cytokine, a decoy receptor for RANKL and a key player in bone homeostasis, has pro-and anti-carcinogenic effects in various types of cancer, including breast neoplasms. In the present study, we have shown that ectopic expression of OPG in breast epithelial/cancer cells promotes the pro-metastatic processes epithelial-to-mesenchymal transition (EMT), stemness, angiogenesis as well as the activation of breast stromal fibroblasts. Furthermore, proteomics analysis, which allows the identification and quantification of a plethora of known and unknown proteins, has shown a strong and significant correlation between OPG upregulation and the expression of proteins with functions in EMT and stemness. On the other hand, OPG knockdown in triple-negative breast cancer (TNBC) cells inhibited the formation of cancer stem cells. Importantly, while OPG upregulation significantly enhanced the resistance of luminal BC cells to cisplatin and docetaxel, OPG downregulation sensitized TNBC cells to these chemotherapeutic drugs. We have also shown that OPG negatively controls estrogen receptor α (ERα), and OPG upregulation correlated well with the expression of genes related to ER-negative claudin low cells. Collectively, these results show that OPG promotes stemness and the consequent chemoresistance of breast cancer cells.