In summary, this study confirmed that HTR1A inhibits the ubiquitin‐proteasome pathway of TβRII by interacting with TRIM21 and PSMD7, simultaneously downregulating the downstream Smad canonical pathway and MEK/ERK/c‐Myc noncanonical pathway, and thus inhibits cytoskeletal rearrangement and EMT to regulate the development of breast cancer. Here, TRIM21 is linked to breast cancer.