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.
雌激素受体α（ER）阳性乳腺癌占美国乳腺癌病例的60%以上。在诊断为早期ER+疾病的患者中，尽管接受了辅助内分泌治疗，仍有三分之一会出现复发。ER是一种核激素受体，负责雌激素驱动的肿瘤生长。ER的转录活性通过与共调节因子的相互作用进行调控。这些共调节因子水平的失调与内分泌耐药性的发展有关。为了识别在乳腺癌中调节ER转录活性的相互作用因子，我们利用生物素连接酶邻近标记技术对ER相互作用组进行了分析。质谱分析显示，含有三方基序的蛋白33（TRIM33）是ER的一个雌激素依赖性相互作用因子。shRNA敲低实验表明，TRIM33促进了ER的转录活性和雌激素诱导的细胞生长。尽管TRIM33已知作为E3泛素连接酶发挥作用，但它增加了乳腺癌细胞内源性ER的稳定性。TRIM33为抑制雌激素诱导的癌细胞生长提供了一个新的靶点，特别是在由ER（ESR1）基因扩增或过表达驱动的内分泌耐药病例中。
肿瘤(癌症)患者之家