Gynecologic and Oncology Peritoneal group, Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; Department of Obstetrics and Gynecology, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain; Department of Obstetrics and Gynecology, Hospital Universitari Son Espases, Palma 07120, Spain.
Gynecologic and Oncology Peritoneal group, Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; Department of Obstetrics and Gynecology, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain.
Gynecol Oncol. 2023 Sep;176:25-35. doi: 10.1016/j.ygyno.2023.06.019. Epub 2023 Jul 11.
Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRβ2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy.
109 EC patients were included. The expression of the ADRβ2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability.
ADRβ2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35-8.88)) and overall survival (HR = 2.98 (95%CI:1.40-6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa).
DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.
儿茶酚胺信号已成为治疗不同类型癌症的靶点。在这项工作中，我们对健康组织和子宫内膜肿瘤中的 ADRβ2、DRD1 和 DRD2 表达进行了特征分析，以评估其在子宫内膜癌 (EC) 中的预后意义，揭示其作为抗肿瘤治疗的可能应用。
纳入 109 例 EC 患者。通过免疫组织化学评估 ADRβ2、DRD1 和 DRD2 蛋白的表达，并进行单变量和多变量分析，以评估其与临床病理和结局变量的关系。最后，将 HEC1A 和 AN3CA EC 细胞系暴露于不同浓度的选择性多巴胺能药物单独或联合使用，以研究其对细胞活力的影响。
ADRβ2 蛋白表达与临床病理参数或预后无关。DRD1 蛋白表达在肿瘤样本中减少，但与肿瘤大小和分期呈显著负相关。DRD2 蛋白表达与非子宫内膜样 EC、高级别肿瘤、肿瘤大小、较差的无病生存 (HR=3.47(95%CI:1.35-8.88))和总生存 (HR=2.98(95%CI:1.40-6.34))显著相关。DRD1 激动剂芬氟拉明在 HEC1A 和 AN3CA 细胞中显示出降低细胞活力的作用。与对照组相比，DRD2 拮抗剂多潘立酮暴露显著降低了细胞活力。最后，与单药治疗相比，DRD1 激动和 DRD2 拮抗联合作用显著降低了 AN3CA 细胞的活力，接近相加反应而不是协同效应 (CI 在 0.5% Fa 时为 1.1)。
DRD1 和 DRD2 表达水平与临床病理参数有显著关联。DRD1 的联合激活和 DRD2 的阻断可能形成抑制 EC 肿瘤生长的创新策略。
