Diosmetin Modulates EMT-Associated Plasticity and Fibroblast-Activation Markers in Parallel Breast Cancer In Vitro Models

Metastasis remains the leading cause of mortality in breast cancer and is closely linked to epithelial–mesenchymal transition (EMT) and tumor microenvironment (TME)-associated processes. Diosmetin (DT), the active metabolite of diosmin, a widely used venoactive drug, has emerged as a potential anticancer agent. Building on our previous findings demonstrating that DT enhances doxorubicin efficacy, this study investigated its effects on tumor cell plasticity and stromal activation-associated responses. EMT was induced in MCF-7 cells, while a stromal model was established by TGF-β-mediated activation of BJ fibroblasts toward a cancer-associated fibroblast (CAF)-like phenotype. Additionally, doxorubicin-induced senescence was generated in fibroblasts. Migration assays and quantitative real-time PCR were used to assess functional and transcriptional changes. EMT induction resulted in decreased CDH1 expression and increased levels of VIM, MMP2, MMP9, IL-6, and HIF-1A, accompanied by enhanced migratory activity. DT attenuated TGF-β-induced CAF-like activation, as reflected by reduced expression of ACTA2, HGF, MMP2, MMP9, and IL6, and modulated hyaluronan turnover-related genes. Moreover, DT partially alleviated selected senescence-associated features in doxorubicin-treated fibroblasts. Collectively, these findings indicate that DT modulates EMT-associated plasticity and stromal activation-related responses in parallel in vitro models. Given its origin as a metabolite of a clinically used compound and its previously demonstrated chemosensitizing properties, DT may warrant further investigation as a potential adjunctive agent to modulate tumor- and stromal-associated processes in breast cancer.