Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in 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.

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

“…This member of the Forkhead family regulates the expression of a large set of G2/M specific genes, and aberrant FOXM1 upregulation has been shown to be a key driver in cancer progression 26 . Our RNA-seq analysis showed an up-regulation of CDK1 , CDK2 , CDK4 , FoxM1, Aurora A/B , but not of CDK3 , CDK5 , CDK6 , genes in MMTV-R26 Met tumours versus normal mammary glands, as reported in TNBC patients 35 , 36 . Nevertheless, their inhibition together with BCL-XL targeting had no effect on the viability of the four MMTV-R26 Met TNBC cell lines we examined.…”

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer

“…It is overexpressed in a broad range of cancer types, including breast cancer, ovarian cancer, glioblastoma, pancreatic cancer, prostate cancer, and GI tract cancers [ 3 , 4 , 5 , 6 ]. Its presence is associated with increased cancer cell proliferation and metastasis [ 7 , 8 , 9 , 10 , 11 ]. Hence, there should be therapeutic benefit from inhibiting the activity of FOXM1 in these cancers.…”

“…Dose ranges from 0.1 to 10 µM were tested in cells in vitro, and IC50 concentrations for suppression of cell proliferation were 0.7–1 µM for NB73 and NB115 [ 11 ]. Furthermore, both compounds showed good pharmacokinetics and long half-lives in mice after s.c. administration [ 11 ], and they suppressed breast tumor xenograft growth and the expression of tumor FOXM1-regulated genes [ 11 ] and tumor metastasis [ 8 ]. We believe that both inhibition of FOXM1 and reduction in the level of FOXM1 in the cancer cells by these inhibitors contribute to their suppression of FOXM1 activity.…”

“…We believe that both inhibition of FOXM1 and reduction in the level of FOXM1 in the cancer cells by these inhibitors contribute to their suppression of FOXM1 activity. Consequently, they diminish the growth and metastasis of breast cancers in preclinical tumor models [ 8 , 11 ].…”

A narrative review of research progress on FoxM1 in breast cancer carcinogenesis and therapeutics

“…Another study by Ziegler et al (153) demonstrated that these novel compounds (including 1,1-diarylethylene mono, diamines, and their corresponding methiodide salts) suppressed FoxM1 activity and breast tumor cell proliferation and growth via cell cycle arrest, and induced apoptosis. Furthermore, Dey et al (154) revealed that the compounds NB-73 and NB-115, through decreasing the expression level of FoxM1 target genes, attenuated the growth, invasiveness, distant metastasis, and the expression of important proteins associated with EMT in TNBC cells.…”