PO.ET02.11 · 实验与分子治疗
CCL5和内皮糖蛋白在ER阳性乳腺癌中的治疗潜力
The therapeutic potential of CCL5 and endoglin in ER-positive breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
雌激素受体（ER）信号驱动约75%的所有乳腺癌，并且仍然是内分泌治疗的核心靶点。然而，治疗抵抗——特别是在携带激活性ESR1配体结合域突变（如Y537S和D538G）的转移性ER阳性肿瘤中——仍然构成重大的临床挑战。这些突变常在内分泌治疗压力下产生，并可在转移灶和循环肿瘤DNA（ctDNA）中被轻易检测到。尽管基于CDK4/6抑制剂的联合治疗改善了患者结局，但维持ESR1突变型肿瘤抵抗的机制及其相关的治疗易感性仍未完全明确。为填补这一空白，我们研究了内分泌抵抗性乳腺癌（ERBC）细胞与肿瘤微环境之间的串扰。使用由七种ERBC细胞系（包括基因组编辑的ESR1突变体）和四种基质细胞类型组成的共培养系统，我们使用细胞因子抗体阵列分析了28对肿瘤-基质分泌组。该分析鉴定出CCL5和内皮糖蛋白在抵抗性肿瘤-基质相互作用中持续上调。我们假设CCL5和内皮糖蛋白通过微环境内的旁分泌信号促进内分泌抵抗和转移进展。为验证这一点，我们通过CRISPR-Cas9生成了CCL5敲除的EO771细胞，并通过qRT-PCR和ELISA验证了CCL5的缺失。CCL5缺陷细胞在体外表现出显著降低的增殖和迁移。在原位小鼠模型中，CCL5敲除肿瘤显示出明显减弱的生长和转移扩散。此外，用CCR5拮抗剂maraviroc和抗CD105单克隆抗体carotuximab处理，选择性地损害了野生型细胞而非CCL5缺陷细胞的活力。总之，这些发现确定CCL5和内皮糖蛋白是ER阳性乳腺癌中内分泌抵抗和转移潜能的关键驱动因素，将它们确立为可干预的治疗靶点。这项工作为未来旨在通过破坏CCL5-内皮糖蛋白信号来克服ESR1突变疾病抵抗的临床策略提供了基础。
查看英文原文 English abstract
Estrogen receptor (ER) signaling drives approximately 75% of all breast cancers and remains the central target of endocrine therapies. However, therapeutic resistance-particularly in metastatic ER-positive tumors harboring activating ESR1 ligand-binding domain mutations such as Y537S and D538G-continues to pose a major clinical challenge. These mutations frequently arise under endocrine treatment pressure and are readily detected in metastatic lesions and circulating tumor DNA (ctDNA). Although CDK4/6 inhibitor-based combination therapies have improved patient outcomes, the mechanisms sustaining resistance in ESR1-mutant tumors and their associated therapeutic vulnerabilities are still not fully defined. To address this gap, we examined the crosstalk between endocrine-resistant breast cancer (ERBC) cells and the tumor microenvironment. Using co-culture systems comprising seven ERBC cell lines-including genome-edited ESR1 mutants-and four stromal cell types, we profiled 28 tumor-stroma secretome pairs using cytokine antibody arrays. This analysis identified CCL5 and endoglin as consistently upregulated in resistant tumor-stroma interactions. We hypothesized that CCL5 and endoglin promote endocrine resistance and metastatic progression through paracrine signaling within the microenvironment. To test this, we generated CCL5-knockout EO771 cells via CRISPR-Cas9 and validated CCL5 loss by qRT-PCR and ELISA. CCL5-deficient cells exhibited significantly reduced proliferation and migration in vitro. In orthotopic mouse models, CCL5 knockout tumors showed markedly diminished growth and metastatic spread. Furthermore, treatment with the CCR5 antagonist maraviroc and the anti-CD105 monoclonal antibody carotuximab selectively impaired the viability of wild-type but not CCL5-deficient cells. Together, these findings identify CCL5 and endoglin as key drivers of endocrine resistance and metastatic potential in ER-positive breast cancer, establishing them as actionable therapeutic targets. This work provides a foundation for future clinical strategies aimed at overcoming resistance in ESR1-mutant disease by disrupting CCL5-endoglin signaling.
利益披露 Disclosure
D. Lomonaco, None..
K. Jin, None.