Tamoxifen resistance remains a clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. Tripartite motif-containing (TRIM) proteins are a new class of SUMO E3 ligases, which regulate the SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and the response to tamoxifen remain unclear. In the present study, we observed that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance. Furthermore, TRIM3 overexpression significantly correlated with poor survival of patients with ER⁺ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking down of TRIM3 reduced these capabilities. Moreover, TRIM3, as a ubiquitin carrier protein 9 (UBC9) binding protein, promoted SUMO modification of estrogen receptor 1 (ESR1) and activated the ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. These results suggest TRIM3 as a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen might provide a potential treatment for breast cancer.

他莫昔芬耐药性仍然是雌激素受体 (ER) 阳性乳腺癌的临床问题。ERα 的 SUMO 化增强了 ERα 诱导的转录活性。三方基序 (TRIM) 蛋白是一类新的 SUMO E3 连接酶，可调节蛋白质的 SUMO 化。然而，TRIM3 在 SUMOylation 中的精确分子机制和功能以及对他莫昔芬的反应仍不清楚。在本研究中，我们观察到 TRIM3 在乳腺癌中显着过度表达，这与他莫昔芬耐药相关。此外，TRIM3 过表达与 ER ⁺患者的不良生存率显着相关。用他莫昔芬治疗的乳腺癌。TRIM3 过表达赋予细胞存活和肿瘤发生，而敲除 TRIM3 会降低这些能力。此外，TRIM3 作为泛素载体蛋白 9 (UBC9) 结合蛋白，促进雌激素受体 1 (ESR1) 的 SUMO 修饰并激活 ER 通路。沉默 UBC9 消除了 TRIM3 在调节他莫昔芬抗性中的功能。这些结果表明TRIM3是乳腺癌治疗的新型生物标志物，表明抑制TRIM3联合他莫昔芬可能为乳腺癌提供潜在的治疗。