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Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer

BACKGROUND: A combination of entinostat, all-trans retinoic acid, and doxorubicin (EAD) induces cell death and differentiation and causes significant regression of xenografts of triple-negative breast cancer (TNBC). METHODS: We investigated the mechanisms underlying the antitumor effects of each com...

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Autores principales: Merino, Vanessa F., Cho, Soonweng, Nguyen, Nguyen, Sadik, Helen, Narayan, Athira, Talbot, Conover, Cope, Leslie, Zhou, Xian C., Zhang, Zhe, Győrffy, Balázs, Sukumar, Saraswati
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263070/
https://www.ncbi.nlm.nih.gov/pubmed/30486871
http://dx.doi.org/10.1186/s13058-018-1068-x
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author Merino, Vanessa F.
Cho, Soonweng
Nguyen, Nguyen
Sadik, Helen
Narayan, Athira
Talbot, Conover
Cope, Leslie
Zhou, Xian C.
Zhang, Zhe
Győrffy, Balázs
Sukumar, Saraswati
author_facet Merino, Vanessa F.
Cho, Soonweng
Nguyen, Nguyen
Sadik, Helen
Narayan, Athira
Talbot, Conover
Cope, Leslie
Zhou, Xian C.
Zhang, Zhe
Győrffy, Balázs
Sukumar, Saraswati
author_sort Merino, Vanessa F.
collection PubMed
description BACKGROUND: A combination of entinostat, all-trans retinoic acid, and doxorubicin (EAD) induces cell death and differentiation and causes significant regression of xenografts of triple-negative breast cancer (TNBC). METHODS: We investigated the mechanisms underlying the antitumor effects of each component of the EAD combination therapy by high-throughput gene expression profiling of drug-treated cells. RESULTS: Microarray analysis showed that entinostat and doxorubicin (ED) altered expression of genes related to growth arrest, inflammation, and differentiation. ED downregulated MYC, E2F, and G2M cell cycle genes. Accordingly, entinostat sensitized the cells to doxorubicin-induced growth arrest at G2. ED induced interferon genes, which correlated with breast tumors containing a higher proportion of tumor-infiltrating lymphocytes. ED also increased the expression of immune checkpoint agonists and cancer testis antigens. Analysis of TNBC xenografts showed that EAD enhanced the inflammation score in nude mice. Among the genes differentially regulated between the EAD and ED groups, an all-trans retinoic acid (ATRA)-regulated gene, DHRS3, was induced in EAD-treated xenografts. DHRS3 was expressed at lower levels in human TNBC metastases compared to normal breast or primary tumors. High expression of ED-induced growth arrest and inflammatory genes was associated with better prognosis in TNBC patients. CONCLUSIONS: Entinostat potentiated doxorubicin-mediated cell death and the combination induced inflammatory signatures. The ED-induced immunomodulation may improve immunotherapy. Addition of ATRA to ED may potentiate inflammation and contribute to TNBC regression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13058-018-1068-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-62630702018-12-05 Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer Merino, Vanessa F. Cho, Soonweng Nguyen, Nguyen Sadik, Helen Narayan, Athira Talbot, Conover Cope, Leslie Zhou, Xian C. Zhang, Zhe Győrffy, Balázs Sukumar, Saraswati Breast Cancer Res Research Article BACKGROUND: A combination of entinostat, all-trans retinoic acid, and doxorubicin (EAD) induces cell death and differentiation and causes significant regression of xenografts of triple-negative breast cancer (TNBC). METHODS: We investigated the mechanisms underlying the antitumor effects of each component of the EAD combination therapy by high-throughput gene expression profiling of drug-treated cells. RESULTS: Microarray analysis showed that entinostat and doxorubicin (ED) altered expression of genes related to growth arrest, inflammation, and differentiation. ED downregulated MYC, E2F, and G2M cell cycle genes. Accordingly, entinostat sensitized the cells to doxorubicin-induced growth arrest at G2. ED induced interferon genes, which correlated with breast tumors containing a higher proportion of tumor-infiltrating lymphocytes. ED also increased the expression of immune checkpoint agonists and cancer testis antigens. Analysis of TNBC xenografts showed that EAD enhanced the inflammation score in nude mice. Among the genes differentially regulated between the EAD and ED groups, an all-trans retinoic acid (ATRA)-regulated gene, DHRS3, was induced in EAD-treated xenografts. DHRS3 was expressed at lower levels in human TNBC metastases compared to normal breast or primary tumors. High expression of ED-induced growth arrest and inflammatory genes was associated with better prognosis in TNBC patients. CONCLUSIONS: Entinostat potentiated doxorubicin-mediated cell death and the combination induced inflammatory signatures. The ED-induced immunomodulation may improve immunotherapy. Addition of ATRA to ED may potentiate inflammation and contribute to TNBC regression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13058-018-1068-x) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-28 2018 /pmc/articles/PMC6263070/ /pubmed/30486871 http://dx.doi.org/10.1186/s13058-018-1068-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Merino, Vanessa F.
Cho, Soonweng
Nguyen, Nguyen
Sadik, Helen
Narayan, Athira
Talbot, Conover
Cope, Leslie
Zhou, Xian C.
Zhang, Zhe
Győrffy, Balázs
Sukumar, Saraswati
Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
title Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
title_full Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
title_fullStr Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
title_full_unstemmed Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
title_short Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
title_sort induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263070/
https://www.ncbi.nlm.nih.gov/pubmed/30486871
http://dx.doi.org/10.1186/s13058-018-1068-x
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