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Breast Cancer Research
Published in: Breast Cancer Research 1/2018

Open Access 01-12-2018 | Research article

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

Authors: Vanessa F. Merino, Soonweng Cho, Nguyen Nguyen, Helen Sadik, Athira Narayan, Conover Talbot Jr, Leslie Cope, Xian C. Zhou, Zhe Zhang, Balázs Győrffy, Saraswati Sukumar

Published in: Breast Cancer Research | Issue 1/2018

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Abstract

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.
Appendix
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Metadata
Title
Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer
Authors
Vanessa F. Merino
Soonweng Cho
Nguyen Nguyen
Helen Sadik
Athira Narayan
Conover Talbot Jr
Leslie Cope
Xian C. Zhou
Zhe Zhang
Balázs Győrffy
Saraswati Sukumar
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-1068-x

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