Cucurbitacin I (JSI‐124)‐dependent inhibition of STAT3 permanently suppresses the pro‐carcinogenic effects of active breast cancer‐associated fibroblasts

Active cancer-associated fibroblasts (CAFs), which constitute the most preponderant cell type in breast tumors, contribute actively to all aspects of cancer progression, stimulate recurrence, and restrain drug sensitivity. In the present study, we tested the effect of the selective JAK/STAT3 inhibitor cucurbitacin I (JSI-124) on active breast CAFs. We have shown that JSI-124 at non-cytotoxic concentration (20 nM) can inhibit the IL-6/STAT3/NF-κB positive feedback loop in breast myofibroblasts, which enabled persistent inactivation of these cells. Interestingly, JSI-124 treatment suppressed the paracrine promotion of the epithelial-to-mesenchymal transition (EMT) process and the pro-migratory/-invasive and -proliferative effects of CAFs on breast cancer cells in vitro. Similarly, JSI-124 inhibited the capacity of CAF cells in promoting tumor growth, EMT, stemness as well as angiogenesis in orthotopic humanized breast cancer tumors. Together, these findings indicate that JSI-124-dependent inhibition of STAT3 could be of great therapeutic value for the treatment of breast cancer through targeting cancer cells as well as their growth supportive stromal fibroblasts and blood vessels. This could pave the path to developing a precise CAF-targeted anticancer therapy.