Cycloechinulin inhibits breast cancer progression via the SGOL2/METTL3/ICAM2 signaling axis and suppresses the growth of breast cancer patient-derived organoids.

Breast cancer (BC) is a notoriously difficult malignancy to treat due to its high molecular heterogeneity and drug resistance. The vast structural diversity of marine-derived compounds remains underutilized in oncology drug development. This study investigates the anti-tumor potential and underlying molecular mechanism of cycloechinulin (CCL), a novel diketopiperazine alkaloid isolated from the marine-derived fungus Aspergillus ochraceus against BC. The anti-cancer efficacy of CCL was evaluated using in vitro phenotypic assays in BC cell lines and validated in patient-derived organoids (PDOs). Global transcriptional changes were profiled via RNA sequencing (RNA-seq), and the clinical significance of downstream targets was analyzed using public patient databases. CCL significantly reduced BC cell viability, suppressed DNA replication, and restricted migration and invasion while inducing cellular apoptosis. CCL treatment also led to robust growth inhibition and morphological degradation across multiple patient-derived breast cancer models. Transcriptomic profiling and bioinformatic validation identified Shugoshin 2 (SGOL2) as a key oncogenic biomarker significantly correlated with advanced clinical stages and poor patient survival. At the molecular level, CCL downregulated the protein expression of SGOL2 as well as its downstream effectors METTL3 and ICAM2. Furthermore, knockdown of SGOL2 reproduced CCL-mediated anti-tumor effects and suppressed METTL3 and ICAM2 expression. In conclusion, CCL suppresses breast cancer progression by inhibiting the novel SGOL2/METTL3/ICAM2 signaling axis. These results present CCL as a promising natural lead compound and a novel chemical scaffold for targeted BC therapeutics.