Identification of FOXM1 as a specific marker for triple‑negative breast cancer.

Abstract

The present study aimed to identify the therapeutic role of the forkhead box M1 (FOXM1)-associated pathway in triple-negative breast cancer (TNBC). Using a Cancer Landscapes-based analysis, a gene regulatory network model was constructed. The present results demonstrated that FOXM1 occupies a key position in gene networks and is a critical regulatory gene in breast cancer. Using breast carcinoma gene expression data from The Cancer Genome Atlas, it was identified that FOXM1 expression was increased in the basal-like breast cancer subtype compared with other breast cancer subtypes. RNA-sequencing analysis of MDA-MB-231 cells treated with 4 and 10 µl/ml Thiostrepton identified 662 and 5,888 significantly differentially expressed genes, respectively. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that FOXM1 was highly associated with multiple biological processes and was markedly associated with metabolic pathways in TNBC. The use of Search Tool for the Retrieval of Interacting Genes/Proteins provided a critical assessment and integration of protein-protein interactions, and demonstrated the multiple important functions of FOXM1 in TNBC. Real-time cell analysis, reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to assess the anti-tumor activity of Thiostrepton in TNBC cells in vitro. The present results identified that suppression of FOXM1 using Thiostrepton inhibited MDA-MB-231 cell proliferation and the expression of cell cycle-associated genes, including cyclin A2, cyclin B2, checkpoint kinase 1, centrosomal protein 55 and polo like kinase 1. Immunofluorescence staining analysis demonstrated that vimentin, filamentous actin and zinc finger E-box-binding homeobox 1 were all decreased following treatment with Thiostrepton. Furthermore, a BALB/C nude mouse subcutaneous xenograft model was used to verify the function of FOXM1 in vivo. The present results demonstrated that FOXM1 inhibition significantly suppressed MDA-MB-231 cell tumorigenesis in vivo. Overall, the present results suggested that FOXM1 is a key gene that serves important roles in multiple biological processes in TNBC and that it may serve as a novel therapeutic target in TNBC.