ophiobolin-a and Breast-Neoplasms

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

Topics: Animals; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Fungi; Gene Expression Regulation, Neoplastic; Humans; Mice, SCID; MicroRNAs; Nuclear Proteins; Phenotype; Sesterterpenes; Twist-Related Protein 1