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. Citation Format: Dominick Lomonaco, Kideok Jin, . The therapeutic potential of CCL5 and endoglin in ER-positive breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7455.
Lomonaco et al. (2026) studied this question.