Protein ubiquitination is an important posttranslational modification that regulates a multitude of cancer related cellular processes, including cell growth and death.Protein ubiquitination is typically sequentially mediated by three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3).The E3 controls substrate specificity.In human beings, there are more than 600 E3s.Interestingly, many E3s undergo frequent genetic and expression aberrations and function as either tumor suppressors (i.e., BRCA1) or oncoproteins (i.e., Mdm2 and Skp2) in breast cancer Several specific and effective small molecular inhibitors of Mdm2 have been reported to have a substantial p53-dependent anti-tumor effect in vivo.Therefore, oncogenic E3s are promising molecules for cancer target therapy.Our long term goal is to identify cancer related E3s as molecular targets and to improve cancer prevention, diagnosis, and therapy.We have recently demonstrated that the WW domain containing E3 ubiquitin protein ligase 1 (WWP 1) gene is frequently amplified and overexpressed in estrogen receptor (ER) positive breast cancer.Inhibition of WWP 1 alone by siRNA or dominant negative WWP 1 induces apoptosis in ER positive breast cancer cell lines MCF7 and HCC1500 primarily through activation of caspase 8.