Collectively, our findings demonstrate that dual-targeting tGLI1 and IL-6/IL-6R/GP130 signaling pathways are effective against HER2-enriched breast cancer and TNBC and support the use of tGLI1 and IL-6/IL-6R/GP130 inhibitors for the treatment of these more aggressive subtypes of breast cancer. Here, ERBB2 is linked to breast cancer.