Therapeutic potential of combined PPARγ agonist and MEK inhibitor treatment in modulating lipid metabolism and adipogenic reprogramming of breast cancer cells.

Breast cancer metastasis is driven by metabolic changes and cellular plasticity, particularly epithelial-mesenchymal transition (EMT). Increasing evidence suggests that increased plasticity due to EMT can be used to reprogram malignant cells toward terminal differentiation. This study investigates the therapeutic potential of Ppar-γ agonists in regulating lipid metabolism and transforming breast cancer cells into post-mitotic, adipocyte-like phenotypes. Using the Py2T mouse breast cancer cell model, EMT was induced with TGF-β, followed by treatment of mesenchymal-like cells with a combination of rosiglitazone (Ppar-γ agonist), trametinib (MEK inhibitor), and paclitaxel (conventional chemotherapeutic agent). Adipogenic phenotypic conversion of the cells was assessed by histological staining (Oil Red O), quantitative PCR, and RNA sequencing targeting 180 genes associated with lipid metabolism and signaling. Our findings demonstrate that mesenchymal breast cancer cells retain significant metabolic plasticity and can be successfully directed towards an adipocyte-like lineage. The combination of rosiglitazone and trametinib significantly increased intracellular lipid accumulation and notably elevated adipogenic markers, including Fabp4 and Ppar-γ. Transcriptomic analysis revealed a coordinated metabolic reprogramming process integrating lipid biosynthesis with cellular motility programs (Itgb3-Itgav) and centered around the Fasn-Srebp1 axis. Furthermore, the addition of paclitaxel consistent with its known antiproliferative pharmacological action, did not further enhance lipid accumulation beyond that observed with rosiglitazone and trametinib alone, while the adipocyte-like phenotype was preserved. In conclusion, this study identifies coordinated changes in lipid metabolism-associated genes during EMT and adipogenic reprogramming of Py2T breast cancer cells. These findings are consistent with a dynamic metabolic regulatory network centered on lipid and sterol metabolism and that warrant further mechanistic validation. Furthermore, they suggest that differentiation-based approaches to target metabolic vulnerabilities and suppress cellular plasticity in aggressive breast cancer subtypes may represent a promising therapeutic strategy that merits further investigation.