Abstract 4414: Targeting CCL5 signaling pathway in endocrine resistant breast cancer therapy

Estrogen receptor (ER) is the primary transcription factor driving ∼75% of all breast cancers and serves as the target for endocrine therapies. However, resistance to endocrine therapy remains a critical clinical challenge, particularly in metastatic ER-positive breast cancers harboring ESR1 point mutations in the ligand-binding domain, such as Y537S and D538G. These mutations are frequently identified in metastatic tumors and circulating tumor DNA (ctDNA) from patients undergoing endocrine treatment. Despite the efficacy of endocrine therapies combined with CDK4/6 inhibitors, resistance mechanisms and therapeutic vulnerabilities in ESR1-mutated metastatic breast cancer remain poorly understood. Our preliminary studies explored the crosstalk between endocrine-resistant breast cancer (ERBC) cells and stromal cells. By co-culturing seven ERBC cell lines, including genome-edited models of ESR1 mutations, with four stromal cell types, we screened 28 secretome combinations using cytokine antibody arrays. This analysis identified significant upregulation of CCL5 and endoglin in the tumor-stromal microenvironment. We hypothesize that CCL5 mediates endocrine therapy resistance and facilitates the metastatic transition of ERBC cells through interactions with stromal components. To test this, we used CRISPR-Cas9 to generate CCL5 knockout EO771 cells and validated the loss of CCL5 expression via qRT-PCR and ELISA. Functional assays revealed significantly reduced proliferation and migration in CCL5 KO cells compared to wild-type cells. In vivo studies using an orthotopic mouse model demonstrated decreased CCL5 KO tumor growth and metastasis, and treatment with maraviroc (a CCR5 inhibitor) selectively reduced wild-type cell viability. These findings establish CCL5 as a critical regulator of ERBC growth and metastasis, supporting its potential as a therapeutic target. This research provides a foundation for designing clinical trials targeting CCL5-mediated resistance mechanisms in endocrine-resistant breast cancer. Citation Format: Dominick Lomonaco, Kideok Jin. Targeting CCL5 signaling pathway in endocrine resistant breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4414.