TY - JOUR
T1 - Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer
AU - Ziegler, Yvonne
AU - Guillen, Valeria Sanabria
AU - Kim, Sung Hoon
AU - Katzenellenbogen, John A.
AU - Katzenellenbogen, Benita S.
N1 - Funding Information:
Funding: This research was supported by grants from the Breast Cancer Research Foundation (BCRF-083 to B.S.K. and BCRF-084 to J.A.K. and B.S.K.), the NIH/NCI (1R01 CA220284 to B.S.K. and J.A.K.), The Julius and Mary Landfield Cancer Research Fund (to BSK), and NIH Training Program T32 GMO70421 Fellowship to V.S.G.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - breast cancer
KW - gene networks and rewiring
KW - FOXM1
KW - growth inhibition
KW - resistance
KW - Resistance
KW - Gene networks and rewiring
KW - Breast cancer
KW - Growth inhibition
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U2 - 10.3390/cancers13246282
DO - 10.3390/cancers13246282
M3 - Article
C2 - 34944900
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 24
M1 - 6282
ER -