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

SIMPLE SUMMARY: The oncogenic transcription factor FOXM1 is overexpressed in many cancers and associated with poor patient outcomes. Hence, there is much interest in blocking FOXM1 activity in cancer. We used small molecule inhibitors of FOXM1 to understand how they impact gene regulatory networks in suppressing cancer cell survival and the rewiring of gene networks that occurs when breast cancer cells become resistant to these compounds. Resistant cells showed reversal of the expression of many genes in the FOXM1 network controlling cell cycle progression, DNA damage repair, and apoptosis and also enhanced inflammatory signaling and upregulated HER2 and EGFR pathways. Targeting some of these factors so as to reduce the inflammatory and growth factor-dominant state of the resistant cancer cells should offer promising approaches for suppressing cancer progression and improving treatment of breast cancer. ABSTRACT: Forkhead box M1 (FOXM1), an oncogenic transcription factor associated with aggressiveness and highly expressed in many cancers, is an emerging therapeutic target. Using novel 1,1-diarylethylene-diammonium small molecule FOXM1 inhibitors, we undertook transcriptomic, protein, and functional analyses to identify mechanisms by which these compounds impact breast cancer growth and survival, and the changes that occur in estrogen receptor (ERα)-positive and triple negative breast cancer cells that acquire resistance upon long-term treatment with the inhibitors. In sensitive cells, these compounds regulated FOXM1 gene networks controlling cell cycle progression, DNA damage repair, and apoptosis. Resistant cells showed transcriptional alterations that reversed the expression of many genes in the FOXM1 network and rewiring that enhanced inflammatory signaling and upregulated HER2 or EGFR growth factor pathways. ERα-positive breast cancer cells that developed resistance 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 benefits and prolong anticancer effectiveness. Improved understanding of how FOXM1 inhibitors suppress breast cancer and how cancer cells can defeat their effectiveness and acquire resistance should be helpful in directing further studies to move these agents towards translation into the clinic.