Wang Xiyin, Emch Michael J, Goetz Matthew P, Hawse John R
Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA.
Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Cancers (Basel). 2025 Jun 25;17(13):2132. doi: 10.3390/cancers17132132.
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.
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.
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.
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.
内分泌药物等靶向治疗显著改善了雌激素受体α阳性（ERα+）乳腺癌患者的预后。不幸的是，对于缺乏ERα和HER2表达的三阴性乳腺癌（TNBC）患者，靶向辅助药物仍然匮乏。我们发现雌激素受体β（ERβ）在约20%的TNBC病例中表达，并且在临床前模型中已证明其激活可抑制增殖、侵袭和迁移。然而，ERβ靶向治疗在化疗耐药发生后是否仍保持疗效尚不清楚。
为解决这个问题，我们构建了对紫杉醇或阿霉素获得性耐药的ERβ+ TNBC细胞系模型。然后我们评估它们对ERβ靶向治疗的反应，并分析与化疗耐药和ERβ配体治疗相关的转录组变化。
化疗耐药的ERβ+ TNBC细胞对ERβ靶向治疗保持敏感性，在某些情况下反应性增强。ERβ表达在未接受过治疗的细胞中不影响化疗疗效。与敏感细胞相比，化疗耐药细胞的转录组发生了巨大变化，令人惊讶的是，尽管维持了ERβ驱动的抗肿瘤活性，但ERβ转录组大幅减少。
这些发现表明，ERβ在化疗难治性疾病中仍然是一个相关的药物靶点，并有助于完善与对ERβ靶向药物反应相关的最小ERβ转录组特征，进一步阐明ERβ发挥其肿瘤抑制作用的主要机制。
