Tripartite Motif-Containing 3 (TRIM3) Enhances ER Signaling and Confers Tamoxifen Resistance in Breast Cancer

Background: Tamoxifen resistance remains a tricky clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. TRIM proteins are a new class of SUMO E3 ligases, regulating SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and response to tamoxifen remains unclear. Methods: : The expression of TRIM3 was assessed in 48 cases with breast cancer which received tamoxifen therapy. The protein and RNA levels of TRIM3 in 12 ER + breast cancer cell lines were assessed by Western blotting and qRT-PCR assays. Effects of TRIM3 in regulating tamoxifen resistance were evaluated both in vitro and in vivo via Cell viability, Colony formation, Anchorage-independent growth ability assays and Tumor xenografts. Molecular mechanism of TRIM3 in regulating SUMOylation of ERα was analyzed by Western blotting, Immunoprecipitation, Far Western blotting and Luciferase activity assays. Results: : We reported that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance., Furthermore,TRIM3 overexpression significantly correlated with poor survival of ER + breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking downTRIM3 reduced these capabilities. Moreover, TRIM3, as a UBC9 binding protein, promoted SUMO modification of ESR1 and activated ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. Conclusions: : These results suggest a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen may provide a potential treatment for breast cancer.