TY - JOUR
T1 - Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
AU - Ziegler, Yvonne
AU - Laws, Mary J.
AU - Sanabria Guillen, Valeria
AU - Kim, Sung Hoon
AU - Dey, Parama
AU - Smith, Brandi P.
AU - Gong, Ping
AU - Bindman, Noah
AU - Zhao, Yuechao
AU - Carlson, Kathryn
AU - Yasuda, Mayuri A.
AU - Singh, Divya
AU - Li, Zhong
AU - El-Ashry, Dorraya
AU - Madak-Erdogan, Zeynep
AU - Katzenellenbogen, John A.
AU - Katzenellenbogen, Benita S.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41523-019-0141-7
DO - 10.1038/s41523-019-0141-7
M3 - Article
C2 - 31815181
AN - SCOPUS:85075971595
SN - 2374-4677
VL - 5
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 45
ER -