Project description:Cancer progression is associated with alterations of epigenetic regulators such as histone-lysine demethylases 4 (KDM4)2-5. During breast cancer therapy, classical treatments fail to address resistant cancer stem cell populations6-10. Here, we identified a novel KDM4 inhibitor (KDM4(i)) with unique preclinical characteristics. KDM4(i) is a highly potent pan KDM4 inhibitor that specifically blocks the demethylase activity of KDM4A, B, C, and D but not that of the other members of the KDM family. We validated the KDM4(i) anti-tumoral properties under conditions recapitulating patient tumors. Therefore, we established a method to isolate and grow triple-negative breast cancer stem cells (BCSCs) from individual patient tumors after neoadjuvant chemotherapy. Limiting dilution orthotopic xenografts of these BCSCs faithfully regenerate original patient tumor histology and gene expression. KDM4(i) blocks proliferation, sphere formation and xenograft tumor growth of BCSCs. Importantly, KDM4(i) abrogates expression of EGFR, a driver of therapy-resistant triple-negative breast tumor cells11, via inhibition of the KDM4A demethylase activity. Taken together, we present a unique BCSC culture system as a basis for therapeutic compound identification and demonstrate that KDM4 inhibition is a new therapeutic strategy for the treatment of triple-negative breast cancer.

2018-04-10 | GSE95042 | GEO

E-GEOD-31138

Project description:Identifying novel anti-angiogenic targets in human breast cancer

2025-01-24 | E-GEOD-31138 | ExpressionAtlas

E-GEOD-52327

Project description:Expression data of ALDH+ breast cancer cells

2025-01-24 | E-GEOD-52327 | ExpressionAtlas

E-GEOD-18773

Project description:CAL-51 breast cancer side population cells

2025-01-24 | E-GEOD-18773 | ExpressionAtlas

E-GEOD-32526

Project description:Expression data from breast cancer tumor-initiating cells