An increase or a decrease in miR-22 expression can resensitize fulvestrant-resistant breast cancer cells to fulvestrant, and signaling circuits involving HER2/NF-κB (p65)/miR-22/HDAC4/p21 and HER2/NF-κB (p65)/miR-22/Ac-p53/p21 may be responsible for this dual role for miR-22 in the constitutive transactivation of p21. This evidence concerns the gene RELA and breast cancer.