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

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 n...

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Autores principales: Ziegler, Yvonne, Laws, Mary J., Sanabria Guillen, Valeria, Kim, Sung Hoon, Dey, Parama, Smith, Brandi P., Gong, Ping, Bindman, Noah, Zhao, Yuechao, Carlson, Kathryn, Yasuda, Mayuri A., Singh, Divya, Li, Zhong, El-Ashry, Dorraya, Madak-Erdogan, Zeynep, Katzenellenbogen, John A., Katzenellenbogen, Benita S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884575/
https://www.ncbi.nlm.nih.gov/pubmed/31815181
http://dx.doi.org/10.1038/s41523-019-0141-7
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author Ziegler, Yvonne
Laws, Mary J.
Sanabria Guillen, Valeria
Kim, Sung Hoon
Dey, Parama
Smith, Brandi P.
Gong, Ping
Bindman, Noah
Zhao, Yuechao
Carlson, Kathryn
Yasuda, Mayuri A.
Singh, Divya
Li, Zhong
El-Ashry, Dorraya
Madak-Erdogan, Zeynep
Katzenellenbogen, John A.
Katzenellenbogen, Benita S.
author_facet Ziegler, Yvonne
Laws, Mary J.
Sanabria Guillen, Valeria
Kim, Sung Hoon
Dey, Parama
Smith, Brandi P.
Gong, Ping
Bindman, Noah
Zhao, Yuechao
Carlson, Kathryn
Yasuda, Mayuri A.
Singh, Divya
Li, Zhong
El-Ashry, Dorraya
Madak-Erdogan, Zeynep
Katzenellenbogen, John A.
Katzenellenbogen, Benita S.
author_sort Ziegler, Yvonne
collection PubMed
description 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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spelling pubmed-68845752019-12-06 Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds Ziegler, Yvonne Laws, Mary J. Sanabria Guillen, Valeria Kim, Sung Hoon Dey, Parama Smith, Brandi P. Gong, Ping Bindman, Noah Zhao, Yuechao Carlson, Kathryn Yasuda, Mayuri A. Singh, Divya Li, Zhong El-Ashry, Dorraya Madak-Erdogan, Zeynep Katzenellenbogen, John A. Katzenellenbogen, Benita S. NPJ Breast Cancer Article 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. Nature Publishing Group UK 2019-11-29 /pmc/articles/PMC6884575/ /pubmed/31815181 http://dx.doi.org/10.1038/s41523-019-0141-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ziegler, Yvonne
Laws, Mary J.
Sanabria Guillen, Valeria
Kim, Sung Hoon
Dey, Parama
Smith, Brandi P.
Gong, Ping
Bindman, Noah
Zhao, Yuechao
Carlson, Kathryn
Yasuda, Mayuri A.
Singh, Divya
Li, Zhong
El-Ashry, Dorraya
Madak-Erdogan, Zeynep
Katzenellenbogen, John A.
Katzenellenbogen, Benita S.
Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
title Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
title_full Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
title_fullStr Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
title_full_unstemmed Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
title_short Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
title_sort suppression of foxm1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884575/
https://www.ncbi.nlm.nih.gov/pubmed/31815181
http://dx.doi.org/10.1038/s41523-019-0141-7
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