Targeting FACT Complex Suppresses Mammary Tumorigenesis in Her2/neu Transgenic Mice

Development of safe and effective tumor-preventive treatments for high-risk patient populations and therapies for early-stage cancer remains a critical need in oncology. We have recently discovered compound with anticancer activity, Curaxin-137, which modulates several important signaling pathways involved in even the very early stages of cancer. In tumor cells, Curaxin-137 inhibits NF-kB- and HSF1-dependent transcription (prosurvival pathways) and activates p53 (a proapoptotic pathway) without inducing DNA damage. These effects result from chromatin trapping and inhibition of activity of the FACT (facilitates chromatin transcription) complex by Curaxin-137. FACT has not been previously implicated in cancer, but we found that its subunits are overexpressed in breast cancer. On the basis of this background, we tested whether Curaxin-137 could suppress tumorigenesis in MMTV-neu transgenic mice, which spontaneously developmammarycarcinomaduetosteroidreceptor–regulatedexpressionoftheHer2proto-oncogene.We foundthatchronicadministrationofCuraxin-137inapreventiveregimentoMMTV-neumicedidnotcause anydetectablechangesinnormalorgansandtissues,yetinhibitedtumoronset,delayedtumorprogression, andprolongedsurvivalofmiceinadose-dependentmanner.Curaxin-137inducedchangesinFACT,altered NF-kBlocalization,andactivatedp53intumorcellsasexpectedfromitsdefinedmechanismofaction.These results support further investigation of Curaxin-137 as a potential preventive and/or early-stage therapeutic agent for breast cancer. Cancer Prev Res; 1–11. � 2012 AACR.