Breast cancer is the most common type of malignancies in women
worldwide, and genotoxic chemotherapeutic drugs are effective by causing DNA
damage in cancer cells. However, >90% of patients with metastatic cancer are resistant
to chemotherapy. The Forkhead box M1 (FOXM1) transcription factor plays a pivotal
role in the resistance of breast cancer cells to chemotherapy by promoting DNA damage
repair following genotoxic drug treatment. The aim of the present study was to
investigate the inhibition of the FOXM1 protein by thiostrepton, a natural antibiotic produced by the Streptomyces species. Experimental studies were designed to examine
the effectiveness of thiostrepton in downregulating FOXM1 mRNA expression and
activity, leading to senescence and apoptosis of breast cancer cells. The cytotoxicity of
thiostrepton in breast cancer was determined using cell viability assay. Additionally,
thiostrepton treatment decreased the mRNA expression of cyclin B1 (CCNB1), a
downstream target of FOXM1. The present results indicated that thiostrepton inhibited
FOXM1 mRNA expression and its effect on CCNB1. Molecular dynamic simulations
were performed to study the interactions between FOXM1-DNA and thiostrepton after
molecular docking. The results revealed that the possible mechanism underlying the
inhibitory effect of thiostrepton on FOXM1 function was by forming a tight complex
with the DNA and FOXM1 via its binding domain. Collectively, these results indicated
that thiostrepton is a specific and direct inhibitor of the FOXM1 protein in breast cancer.
The findings of the present study may lead to the development of novel therapeutic
strategies for breast cancer and help overcome resistance to conventional
chemotherapeutic drugs.