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Histone deacetylase inhibitor entinostat in combination with a retinoid downregulates HER2 and reduces the tumor initiating cell population in aromatase inhibitor-resistant breast cancer.

Abstract
Resistance to aromatase inhibitors (AIs) involves increased HER2. One mechanism by which HER2 may mediate resistance is through expansion of the tumor initiating cell (TIC) population. This study investigates whether combining all-trans retinoic acid (ATRA) and histone deacetylase inhibitor entinostat (ENT) can inhibit TICs and HER2 in AI-resistant cells and tumors. Modulation of cell viability and HER2 expression were assessed in AI-resistant cells treated with ATRA + ENT. Letrozole-resistant LTLT-Ca cells treated with ATRA + ENT were assayed for changes in TIC characteristics, such as TIC markers (BCRP, ALDH, and BMI-1), side population (SP), and mammosphere formation. Xenograft tumors of MCF-7Ca cells made resistant to letrozole were treated with ATRA, ATRA + letrozole, ATRA + ENT, or ATRA + ENT + letrozole. Resulting tumors were assayed for changes in TIC characteristics. Patient samples taken pre- and post-AI treatment were analyzed for changes in ERα and HER2 protein expression. Treatment with ATRA + ENT reduced HER2 expression and viability (P < 0.001) in AI-resistant cells, as well as decreased SP (P < 0.0001), mammosphere formation (P < 0.01), and expression of TIC molecular markers (P < 0.01) in LTLT-Ca. A reduction in tumor growth rate was observed in mice treated with ENT + ATRA + letrozole when compared to mice treated with single agents (P < 0.0001) or ENT + ATRA (P = 0.02). Decreased TIC characteristics, including mammosphere formation (P < 0.05), were observed in tumors from the triple combination. An increase in HER2 and downregulation in ERα protein expression was observed in patients upon resistance to AI (P < 0.005). These studies indicate that the combination of ATRA and ENT inhibits the TIC population of AI-resistant cells and may be effective in reducing tumor recurrence.
AuthorsAmanda J Schech, Preeti Shah, Stephen Yu, Gauri J Sabnis, Olga Goloubeva, Paula Rosenblatt, Armina Kazi, Saranya Chumsri, Angela Brodie
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 152 Issue 3 Pg. 499-508 (Aug 2015) ISSN: 1573-7217 [Electronic] Netherlands
PMID26133921 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Aromatase Inhibitors
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Nitriles
  • Pyridines
  • Triazoles
  • entinostat
  • Tretinoin
  • Letrozole
  • ERBB2 protein, human
  • Receptor, ErbB-2
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Aromatase Inhibitors (pharmacology)
  • Benzamides (administration & dosage, pharmacology)
  • Breast Neoplasms (drug therapy, pathology)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm (drug effects)
  • Female
  • Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
  • Humans
  • Letrozole
  • Mice, Nude
  • Nitriles (pharmacology)
  • Pyridines (administration & dosage, pharmacology)
  • Receptor, ErbB-2 (metabolism)
  • Tretinoin (administration & dosage)
  • Triazoles (pharmacology)
  • Xenograft Model Antitumor Assays

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