Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple-negative breast cancer

Vanessa F. Merino, Nguyen Nguyen, Kideok Jin, Helen Sadik, Soonweng Cho, Preethi Korangath, Liangfeng Han, Yolanda M.N. Foster, Xian C. Zhou, Zhe Zhang, Roisin M. Connolly, Vered Stearns, Syed Z. Ali, Christina Adams, Qian Chen, Duojia Pan, David L. Huso, Peter Ordentlich, Angela Brodie, Saraswati Sukumar

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Efforts to induce the differentiation of cancer stem cells through treatment with all-trans retinoic acid (ATRA) have yielded limited success, partially due to the epigenetic silencing of the retinoic acid receptor (RAR)-β. The histone deacetylase inhibitor entinostat is emerging as a promising antitumor agent when added to the standard-of-care treatment for breast cancer. However, the combination of epigenetic, cellular differentiation, and chemotherapeutic approaches against triple-negative breast cancer (TNBC) has not been investigated. In this study, we found that combined treatment of TNBC xenografts with entinostat, ATRA, and doxorubicin (EAD) resulted in significant tumor regression and restoration of epigenetically silenced RAR-β expression. Entinostat and doxorubicin treatment inhibited topoisomerase II-β (TopoII-β) and relieved TopoII-β-mediated transcriptional silencing of RAR-β. Notably, EAD was the most effective combination in inducing differentiation of breast tumor-initiating cells in vivo. Furthermore, gene expression analysis revealed that the epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate proliferation and differentiation, enhanced cell differentiation in response to EAD triple therapy. Finally, we demonstrate that patient-derived metastatic cells also responded to treatment with EAD. Collectively, our findings strongly suggest that entinostat potentiates doxorubicin-mediated cytotoxicity and retinoid-driven differentiation to achieve significant tumor regression in TNBC.

Original languageEnglish (US)
Pages (from-to)2013-2024
Number of pages12
JournalCancer Research
Volume76
Issue number7
DOIs
StatePublished - Apr 1 2016

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Triple Negative Breast Neoplasms
Neoplastic Stem Cells
Epigenomics
Doxorubicin
Retinoic Acid Receptors
Type II DNA Topoisomerase
Tretinoin
Therapeutics
Breast Neoplasms
Histone Deacetylase Inhibitors
Retinoids
Standard of Care
entinostat
Heterografts
Antineoplastic Agents
Cell Differentiation
Neoplasms
Transcription Factors
Epithelium
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple-negative breast cancer. / Merino, Vanessa F.; Nguyen, Nguyen; Jin, Kideok; Sadik, Helen; Cho, Soonweng; Korangath, Preethi; Han, Liangfeng; Foster, Yolanda M.N.; Zhou, Xian C.; Zhang, Zhe; Connolly, Roisin M.; Stearns, Vered; Ali, Syed Z.; Adams, Christina; Chen, Qian; Pan, Duojia; Huso, David L.; Ordentlich, Peter; Brodie, Angela; Sukumar, Saraswati.

In: Cancer Research, Vol. 76, No. 7, 01.04.2016, p. 2013-2024.

Research output: Contribution to journalArticle

Merino, VF, Nguyen, N, Jin, K, Sadik, H, Cho, S, Korangath, P, Han, L, Foster, YMN, Zhou, XC, Zhang, Z, Connolly, RM, Stearns, V, Ali, SZ, Adams, C, Chen, Q, Pan, D, Huso, DL, Ordentlich, P, Brodie, A & Sukumar, S 2016, 'Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple-negative breast cancer', Cancer Research, vol. 76, no. 7, pp. 2013-2024. https://doi.org/10.1158/0008-5472.CAN-15-1619
Merino, Vanessa F. ; Nguyen, Nguyen ; Jin, Kideok ; Sadik, Helen ; Cho, Soonweng ; Korangath, Preethi ; Han, Liangfeng ; Foster, Yolanda M.N. ; Zhou, Xian C. ; Zhang, Zhe ; Connolly, Roisin M. ; Stearns, Vered ; Ali, Syed Z. ; Adams, Christina ; Chen, Qian ; Pan, Duojia ; Huso, David L. ; Ordentlich, Peter ; Brodie, Angela ; Sukumar, Saraswati. / Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple-negative breast cancer. In: Cancer Research. 2016 ; Vol. 76, No. 7. pp. 2013-2024.
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abstract = "Efforts to induce the differentiation of cancer stem cells through treatment with all-trans retinoic acid (ATRA) have yielded limited success, partially due to the epigenetic silencing of the retinoic acid receptor (RAR)-β. The histone deacetylase inhibitor entinostat is emerging as a promising antitumor agent when added to the standard-of-care treatment for breast cancer. However, the combination of epigenetic, cellular differentiation, and chemotherapeutic approaches against triple-negative breast cancer (TNBC) has not been investigated. In this study, we found that combined treatment of TNBC xenografts with entinostat, ATRA, and doxorubicin (EAD) resulted in significant tumor regression and restoration of epigenetically silenced RAR-β expression. Entinostat and doxorubicin treatment inhibited topoisomerase II-β (TopoII-β) and relieved TopoII-β-mediated transcriptional silencing of RAR-β. Notably, EAD was the most effective combination in inducing differentiation of breast tumor-initiating cells in vivo. Furthermore, gene expression analysis revealed that the epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate proliferation and differentiation, enhanced cell differentiation in response to EAD triple therapy. Finally, we demonstrate that patient-derived metastatic cells also responded to treatment with EAD. Collectively, our findings strongly suggest that entinostat potentiates doxorubicin-mediated cytotoxicity and retinoid-driven differentiation to achieve significant tumor regression in TNBC.",
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AU - Sadik, Helen

AU - Cho, Soonweng

AU - Korangath, Preethi

AU - Han, Liangfeng

AU - Foster, Yolanda M.N.

AU - Zhou, Xian C.

AU - Zhang, Zhe

AU - Connolly, Roisin M.

AU - Stearns, Vered

AU - Ali, Syed Z.

AU - Adams, Christina

AU - Chen, Qian

AU - Pan, Duojia

AU - Huso, David L.

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AU - Brodie, Angela

AU - Sukumar, Saraswati

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