Background: Targeted therapies, such as endocrine agents, have significantly improved outcomes for patients with estrogen receptor alpha-positive (ERα+) breast cancer. Unfortunately, for patients with triple-negative breast cancer (TNBC), which lack expression of ERα and HER2, there remains a dearth of targeted adjuvant agents. We discovered that estrogen receptor beta (ERβ) is expressed in approximately 20% of TNBC cases, and its activation has been shown to inhibit proliferation, invasion, and migration in preclinical models. However, it remains unclear whether ERβ-targeted therapies maintain efficacy following the development of chemoresistance. Methods: To address this question, we generated ERβ+ TNBC cell line models with acquired resistance to paclitaxel or doxorubicin. We then assessed their response to ERβ-targeted therapies and analyzed transcriptomic changes associated with chemoresistance and ERβ ligand treatment. Results: Chemotherapy-resistant ERβ+ TNBC cells retained sensitivity to ERβ-targeted therapies and, in some cases, exhibited enhanced responsiveness. ERβ expression did not compromise chemotherapy efficacy in treatment-naïve cells. Chemotherapy-resistant cells had a vastly altered transcriptome and surprisingly, a heavily reduced ERβ transcriptome, compared to sensitive cells despite the maintenance of ERβ-driven anti-neoplastic activity. Conclusions: These findings suggest that ERβ remains a relevant drug target in chemotherapy-refractory disease and has aided in the refinement of a minimal ERβ transcriptomic signature associated with response to ERβ-targeting agents, further informing the primary mechanisms through which ERβ elicits its tumor suppressive effects.
背景：针对雌激素受体α阳性（ERα+）乳腺癌患者，内分泌药物等靶向治疗已显著改善其预后。然而，对于缺乏ERα和HER2表达的三阴性乳腺癌（TNBC）患者，目前仍缺乏有效的靶向辅助治疗药物。我们发现，约20%的TNBC病例表达雌激素受体β（ERβ），临床前模型显示其激活可抑制肿瘤增殖、侵袭和迁移。但ERβ靶向治疗在化疗耐药后是否仍保持疗效尚不明确。方法：为探究此问题，我们构建了对紫杉醇或多柔比星获得性耐药的ERβ+ TNBC细胞系模型，评估其对ERβ靶向治疗的反应，并分析与化疗耐药及ERβ配体治疗相关的转录组变化。结果：耐化疗的ERβ+ TNBC细胞仍对ERβ靶向治疗保持敏感性，部分甚至表现出增强的反应性。在未经过治疗的细胞中，ERβ表达不影响化疗疗效。与敏感细胞相比，耐药细胞的转录组发生显著改变，且尽管ERβ驱动的抗肿瘤活性得以维持，其ERβ转录组却意外大幅减少。结论：这些发现表明ERβ在化疗耐药疾病中仍是相关药物靶点，并有助于完善与ERβ靶向药物反应相关的最小ERβ转录组特征，进一步阐明ERβ发挥肿瘤抑制效应的主要机制。
Anti-Neoplastic Activity of Estrogen Receptor Beta in Chemoresistant Triple-Negative Breast Cancer
肿瘤(癌症)患者之家