Abstract
BackgroundA 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).MethodsWe 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.ResultsMicroarray 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.ConclusionsEntinostat 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.
Highlights
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)
Entinostat and doxorubicin combination induces gene reprogramming Previously, we showed that a combination of entinostat, All-trans retinoic acid (ATRA), and doxorubicin (EAD) resulted in increased cell death and differentiation, and as a consequence, a decrease of tumor volume [20]
To explore additional mechanisms of tumor regression caused by EAD, and to identify drug targets other than RAR-β, we performed high-throughput gene expression profiling analysis of MDA-MB-231 cells treated with entinostat, ATRA, and doxorubicin as single, double, and triple combinations
Summary
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). All-trans retinoic acid (ATRA) induces breast cancer differentiation [1, 2], cell death [3], and inflammation [4]. We and others have shown that RAR-β is underexpressed and epigenetically silenced in breast cancer, and that histone deacetylase inhibitors (HDACi) cause reexpression of RAR-β and sensitize the cells to treatment [8, 9]. HDACi are currently employed in the clinic for the treatment of a wide variety of solid and hematological malignancies [10], including breast cancer [11]. HDACi have been shown to enhance the immunogenicity of cancer cells [17]
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