CXCR4 and breast cancer: With regard to E3 ubiquitin ligase ITCH of Notch3, research has shown that[63] ITCH can regulate the degradation of the tumor suppressor gene p63 and its improper removal is also closely related to malignant transformation and chemical resistance.[64] However, it has also been reported that[59] the activation of ITCH can mediate the ubiquitination and endocytosis of the chemokine receptor CXCR4, thereby reducing the stemness of breast cancer cells.