Cancer-associated fibroblasts induce growth and radioresistance of breast cancer cells through paracrine IL-6

In breast cancer, the most numerous stromal cells are cancer-associated fibroblasts (CAFs), which are associated with disease progression and chemoresistance. However, few studies have explored the function of CAFs in breast cancer cell radiosensitivity. Here, CAF-derived conditioned media was observed to induce breast cancer cell growth and radioresistance. CAFs secrete interleukin 6 (IL-6) which activates signal transducer and activator of transcription 3 (STAT3) signaling pathway, thus promoting the growth and radioresistance of breast cancer cells. Treatment with an inhibitor of STAT3 or an IL-6 neutralizing antibody blocked the growth and radioresistance induced by CAFs. In in vivo mouse models, tocilizumab (an IL-6 receptor monoclonal antibody) abrogated CAF-induced growth and radioresistance. Moreover, in breast cancer, a poor response to radiotherapy was associated with IL-6 and p-STAT3 expression. These results indicated that IL-6 mediates cross-talk between breast cancer cells and CAFs in the tumor microenvironment. Our results identified the IL-6/STAT3 signaling pathway as an important therapeutic target in breast cancer radiotherapy.

Automated summary

Cancer-associated fibroblasts (CAFs) are the most common stromal cells in breast cancer, and they play a role in disease progression and chemoresistance. This study found that CAF-derived conditioned media can promote breast cancer cell growth and radioresistance. The secretion of interleukin 6 (IL-6) by CAFs activates the STAT3 signaling pathway, leading to the growth and radioresistance of breast cancer cells. Inhibition of STAT3 or neutralizing IL-6 can block the effects induced by CAFs. In mouse models, the IL-6 receptor monoclonal antibody tocilizumab can reverse CAF-induced growth and radioresistance. Additionally, poor response to radiotherapy in breast cancer is associated with the expression of IL-6 and p-STAT3. These findings highlight the importance of the IL-6/STAT3 signaling pathway as a potential therapeutic target in breast cancer radiotherapy.