This review highlights the important roles of TRIMs in cancer initiation, development, and progression, and conducts an intensive and comprehensive investigation of the potential clinical implications and regulatory mechanisms by which TRIMs contribute to the dysregulation of various signaling pathways including JAK/STAT, PI3K/AKT, TGF-β, NF-κB, Wnt/β-catenin, and p53. The gene discussed is PIK3CA; the disease is cancer.