Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in Triple Negative Breast Cancer

SIMPLE SUMMARY: Triple negative breast cancer is an aggressive subtype of breast cancer that frequently metastasizes. Because the transcription factor FOXM1 is highly upregulated in triple negative breast cancer and controls many cell activities that lead to cancer progression and metastasis, we sought to determine if FOXM1 inhibitory compounds could effectively suppress the invasiveness and progression of triple negative breast cancer cells and tumors. Our findings show that these compounds inhibit cell motility, invasiveness, and the expression of important proteins associated with epithelial to mesenchymal transition. These compounds also suppressed the proliferation and metastatic outgrowth of triple negative breast tumors. Thus, these findings highlight the crucial role of FOXM1 in promoting the progression and metastasis of these cancers, and suggest that FOXM1 inhibitory compounds may have therapeutic potential and prove beneficial in intervention against triple negative breast cancer. ABSTRACT: Metastasis-related complications account for the overwhelming majority of breast cancer mortalities. Triple negative breast cancer (TNBC), the most aggressive breast cancer subtype, has a high propensity to metastasize to distant organs, leading to poor patient survival. The forkhead transcription factor, FOXM1, is especially upregulated and overexpressed in TNBC and is known to regulate multiple signaling pathways that control many key cancer properties, including proliferation, invasiveness, stem cell renewal, and therapy resistance, making FOXM1 a critical therapeutic target for TNBC. In this study, we test the effectiveness of a novel class of 1,1-diarylethylene FOXM1 inhibitory compounds in suppressing TNBC cell migration, invasion, and metastasis using in vitro cell culture and in vivo tumor models. We show that these compounds inhibit the motility and invasiveness of TNBC MDA-MB-231 and DT28 cells, along with reducing the expression of important epithelial to mesenchymal transition (EMT) associated genes. Further, orthotopic tumor studies in NOD-SCID-gamma (NSG) mice demonstrate that these compounds reduce FOXM1 expression and suppress TNBC tumor growth as well as distant metastasis. Gene expression and protein analyses confirm the decreased levels of EMT factors and FOXM1-regulated target genes in tumors and metastatic lesions in the inhibitor-treated animals. The findings suggest that these FOXM1 suppressive compounds may have therapeutic potential in treating triple negative breast cancer, with the aim of reducing tumor progression and metastatic outgrowth.