Targeting P53-Driven FOXM1 Suppresses Tumor Growth and Synergistically Sensitizes to Chemotherapy in Triple-Negative Breast Cancer Models

Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen, progesterone, and HER2 receptors; an aggressive phenotype; high rates of early relapse and metastasis; and the worst mortality rates among all breast cancer subtypes. Currently, there is no effective curative targeted therapy for TNBC and chemotherapy remains the primary treatment for TNBC. Therefore, there is a critical need to develop highly effective, novel therapies to improve patient survival. We previously validated FOXM1, a proto-oncogenic transcription factor, for the first time as a potential molecular target in TNBC through genetic knockdown studies in mice. We show that FOXM1 expression is associated with shorter patient survival and is a marker of poor prognosis. There is no FDA-approved FOXM1 inhibitor. We found that patients with TP53 mutations have dramatically higher FOXM1 expression, indicating that widespread TP53 mutations detected in about 80% of TNBC patients are the major driver of FOXM1 overexpression in TNBC patients. We identified its binding ability using an in silico study, and found it to be a well-known FOXM1 inhibitor that suppresses TNBC cell proliferation, migration, and invasion, and induces apoptosis. In vivo studies in mice bearing TNBC tumors demonstrated that treatment with a novel FOXM1 inhibitor incorporated in single-lipid nanoparticles suppressed the growth of TNBC tumor xenografts. In conclusion, our findings suggest that the novel FOXM1 inhibitor represents a potent and safe therapeutic strategy with significant potential for the treatment of other FOXM1-driven cancers including TNBC that currently have limited treatment options.