Meanwhile, CXCL6 induces more CLCF1 secretion, forming a positive feedback loop.212 Moreover, CAFs in luminal-like HER2+ breast cancer cell lines can release NRG1β, which binds to HER3 and stabilizes the HER2-HER3 dimer to maintain everlasting activation of downstream pathways, resulting in lapatinib resistance.213 In refractory tumors, CAFs promote tumor angiogenesis and progression despite administrating VEGFR TKIs,214 suggesting the existence of VEGFR-independent PDGFR-related angiogenesis pathways. This evidence concerns the gene ERBB3 and breast cancer.