Also mechanistically, in prostate cancer cell lines such as LNCaP and PC3 cells, dihydrotestosterone (DHT)-induced AR transactivation can form a complex with SMAD3 and SMAD4, where SMAD3/AR complexes promote transcription via DNA binding to AREs, while SMAD3/SMAD4/AR complexes inhibit androgen target gene expression.150 Hayes et al.167 observed a repression of androgen target gene expression by SMAD3/AR complexes, by direct binding of the MH2 domain of SMAD3 with the transcription activation domain of the AR. Here, SMAD4 is linked to Familial prostate cancer.