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

Vanessa F. Merino, Soonweng Cho, Nguyen Nguyen, Helen Sadik, Athira Narayan, Conover Talbot, Leslie Cope, Xian C. Zhou, Zhe Zhang, B. Györffy, Saraswati Sukumar

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number1068
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
Publication statusPublished - Nov 28 2018

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Triple Negative Breast Neoplasms
Cell Cycle Checkpoints
Epigenomics
Doxorubicin
Genes
Tretinoin
Heterografts
Therapeutics
Inflammation
entinostat
Cell Death
Growth
Tumor-Infiltrating Lymphocytes
cdc Genes
Immunomodulation
Testicular Neoplasms
Gene Expression Profiling
Microarray Analysis
Nude Mice
Immunotherapy

Keywords

  • Breast cancer
  • Entinostat
  • Epigenetic
  • Immunotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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; Györffy, B.; Sukumar, Saraswati.

In: Breast Cancer Research, Vol. 20, No. 1, 1068, 28.11.2018.

Research output: Contribution to journalArticle

Merino, Vanessa F. ; Cho, Soonweng ; Nguyen, Nguyen ; Sadik, Helen ; Narayan, Athira ; Talbot, Conover ; Cope, Leslie ; Zhou, Xian C. ; Zhang, Zhe ; Györffy, B. ; Sukumar, Saraswati. / Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer. In: Breast Cancer Research. 2018 ; Vol. 20, No. 1.
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AU - Sadik, Helen

AU - Narayan, Athira

AU - Talbot, Conover

AU - Cope, Leslie

AU - Zhou, Xian C.

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AU - Sukumar, Saraswati

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AB - 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.

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