Transcription regulation and genome rewiring governing sensitivity and resistance to FOXM1 inhibition in breast cancer I

Forkhead box M1 (FOXM1) is an oncogenic transcription factor overexpressed in many cancers and associated with aggressiveness. Using 1,1-diarylethylene-diammonium compounds that suppress FOXM1 activity, we utilized genome-wide transcriptomic, protein analyses, and functional approaches to identify mechanisms by which these compounds inhibit breast cancer growth and survival. These compounds downregulated FOXM1 gene networks in estrogen receptor (ER)-positive and triple negative breast cancer (TNBC) cells, and RNA-Seq and pathway analyses revealed that cell cycle progression, DNA damage repair, and apoptosis were most greatly affected, in agreement with the cancer promoting functions of FOXM1. TNBC and ER-positive breast cancer cells grown long-term with the inhibitors developed resistance. Notably, resistant cells showed transcriptional alterations and rewiring leading to reversal of the regulation of many genes in the FOXM1 network and marked changes in inflammatory signaling and HER2 and EGFR signature genes and pathways. High expression of a 43-gene Interferon-Related FOXM1 inhibitor resistance Signature (IRFMS) derived from ER-positive inhibitor resistant cells predicted a less good prognosis and poorer survival in patients with ER-positive breast cancer. Resistant cells showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefit and enable prolonged anticancer effectiveness. Examine how the development of resistance to FOXM1 inhibitors results in changes in gene expression in both estrogen receptor positive and triple negative cancer cell lines.