Toll-Like Receptor 2 Promotes Breast Cancer Progression and Resistance to Chemotherapy
Abstract Background. Breast cancer (BC) is the leading cause of cancer death in women, due to the development of resistance to current therapies, including chemotherapy. Since breast cancer stem cells (CSCs) are the main drivers of therapy resistance and disease progression, chemoresistance might be prevented targeting the molecules that promote their self-renewal. We previously demonstrated that Toll-like Receptor (TLR)2 is overexpressed in CSCs, which exploit it to promote their self-renewal through an autocrine loop initiated by high mobility group box (HMGB)1. TLR2 expression in BC is associated with poor prognosis in patients, suggesting that it could be a good target for BC therapies.Methods. We generated and characterized TLR2WT and TLR2KO autochthonous mammary cancer mouse models. In-vitro and in-vivo studies were performed to assess the efficacy of TLR2 silencing and inhibition in combination with chemotherapy.Results. TLR2KO mice displayed delayed tumor onset, increased survival, and reductions in CSC and T regulatory cell frequency, compared to TLR2WT mice. Transplantation experiments using TLR2WT and TLR2KO cells injected subcutaneously into TLR2WT and TLR2KO mice showed that TLR2 mainly acts via cancer-cell-intrinsic mechanisms, such as increased cell survival and CSC self-renewal. Moreover, TLR2 promoted cancer cell resistance to chemotherapy following the doxorubicin-induced release of HMGB1. Thus, TLR2 inhibitors impaired the viability and induced the apoptosis of BC cells and exerted a synergistic effect when administered with chemotherapy both in-vitro and in-vivo. Conclusions. We have demonstrated that TLR2 inhibitors reinstate BC response to chemotherapy, opening new perspectives for the treatment of BC patients.