The suppression of FOXM1 and its targets in breast cancer xenograft tumors by siRNA

Abstract

As an oncogenic transcription factor, the Forkhead box protein M1 (FOXM1) is overexpressed in human tumors.  FOXM1 promotes tumorigenesis by regulating genes associated with cell cycle progression and cell proliferation, and its inhibition in cell lines has been shown to sensitize cells to apoptosis.  In this report, we examined the possibility of suppressing FOXM1 in tumors in vivo, through the administration of FoxM1-specific siRNA.  Firstly, we determined the functionality of siRNA treatment in subcutaneous MDA-MB-231-luc breast cancer tumors.  We found that upon encapsulation into a PEI-based delivery agent, fluorescently-labeled siRNA was retained within tumors when administered intratumorally.  Injection of anti-luciferase siRNA was also able to suppress tumor-associated luciferase for at least 48 hours.  More importantly, repeat administrations of PEI-encapsulated anti-FoxM1 siRNA resulted in the reduced expression of FOXM1 protein levels in tumors.  In addition, both the protein levels and mRNA levels of cdc25B and Aurora B Kinase, transcriptional targets of FOXM1 were also reduced in tumors treated with anti-FoxM1 siRNA.  p27, an indirect target of FOXM1 associated with growth inhibition was further found be increased in tumors treated with FoxM1-siRNA.  Our data suggests that anti-FoxM1 siRNA can be functional when administered into tumors in an in vivo system, and that anti-FoxM1 siRNA holds potential as part of a therapy for cancer treatment.