Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds

Yvonne Ziegler, Mary J. Laws, Valeria Sanabria Guillen, Sung Hoon Kim, Parama Dey, Brandi P. Smith, Ping Gong, Noah Bindman, Yuechao Zhao, Kathryn Carlson, Mayuri A. Yasuda, Divya Singh, Zhong Li, Dorraya El-Ashry, Zeynep Madak-Erdogan, John A. Katzenellenbogen, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

The transcription factor FOXM1 is upregulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome- dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.

Original languageEnglish (US)
Article number45
Journalnpj Breast Cancer
Volume5
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

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    Ziegler, Y., Laws, M. J., Sanabria Guillen, V., Kim, S. H., Dey, P., Smith, B. P., Gong, P., Bindman, N., Zhao, Y., Carlson, K., Yasuda, M. A., Singh, D., Li, Z., El-Ashry, D., Madak-Erdogan, Z., Katzenellenbogen, J. A., & Katzenellenbogen, B. S. (2019). Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds. npj Breast Cancer, 5(1), [45]. https://doi.org/10.1038/s41523-019-0141-7