Targeting the CCL5/CCR5-PI3K-AKT axis suppresses hepatic stellate cell-induced breast cancer metastasis

BACKGROUND: Breast cancer liver metastasis is a major contributor to cancer-related death; however, the function of hepatic stellate cells (HSCs) in shaping the metastatic microenvironment remains poorly understood. This study investigates how HSC-secreted CCL5 activates the PI3K-AKT pathway via CCR5 to drive breast cancer invasion and metastasis. METHODS: In vitro co-culture models of HSCs with MDA-MB-231 and MCF-7 cells were employed, alongside Transwell migration/invasion assays. Conditioned medium (CM) from activated HSCs was used to assess tumor cell behavior. CCR5 and PI3K-AKT inhibitors (Maraviroc, BKM120) and siRNA-mediated gene silencing were applied to dissect molecular mechanisms. In vivo models, including liver metastasis assays and xenografts using CM-pretreated breast cancer cells, evaluated tumor colonization and growth. Bioinformatics analysis of TCGA data correlated CCL5 expression with clinical outcomes. RESULTS: Breast cancer cells induced the activation of HSCs, triggering the secretion of CCL5. This HSC-derived CCL5 significantly enhanced tumor cell growth, motility, invasiveness, and epithelial-mesenchymal transition (EMT) by binding to CCR5 and activating the PI3K-AKT pathway. Conversely, silencing CCL5 in HSCs or CCR5 in tumor cells suppressed these malignant behaviors and inhibited PI3K-AKT phosphorylation. In vivo, blocking this axis attenuated tumor growth and liver metastasis. Notably, the anti-tumor effects of CCR5 inhibition were reversed by the PI3K activator 740 Y-P, confirming mechanism specificity. Clinical analysis revealed that elevated CCL5 expression correlates with poor prognosis in breast cancer patients. CONCLUSIONS: This study identifies a critical stromal-tumor signaling loop where the HSC-CCL5/CCR5 axis drives breast cancer metastasis via PI3K-AKT-dependent EMT. Targeting this crosstalk represents a promising therapeutic strategy for preventing liver metastasis.