TRIM33 Is a Co-Regulator of Estrogen Receptor Alpha

Simple Summary Dysregulation of estrogen receptor alpha (ER) activity has been implicated in the development of resistance to current treatment strategies. The purpose of this study was to profile novel coregulatory proteins to identify potential therapeutic targets. We identified TRIM33 as a novel interactor and regulator of ER activity and protein stability. These results provide rationale for further investigation of the role of TRIM33 in cancers exhibiting increased ER protein levels.Abstract Estrogen receptor alpha (ER)-positive breast cancer is responsible for over 60% of breast cancer cases in the U.S. Among patients diagnosed with early-stage ER+ disease, 1/3 will experience recurrence despite treatment with adjuvant endocrine therapy. ER is a nuclear hormone receptor responsible for estrogen-driven tumor growth. ER transcriptional activity is modulated by interactions with coregulators. Dysregulation of the levels of these coregulators is involved in the development of endocrine resistance. To identify ER interactors that modulate transcriptional activity in breast cancer, we utilized biotin ligase proximity profiling of ER interactomes. Mass spectrometry analysis revealed tripartite motif containing 33 (TRIM33) as an estrogen-dependent interactor of ER. shRNA knockdown showed that TRIM33 promoted ER transcriptional activity and estrogen-induced cell growth. Despite its known role as an E3 ubiquitin ligase, TRIM33 increased the stability of endogenous ER in breast cancer cells. TRIM33 offers a novel target for inhibiting estrogen-induced cancer cell growth, particularly in cases of endocrine resistance driven by ER (ESR1) gene amplification or overexpression.