Functional activation of the estrogen receptor-α and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole.

Approximately 25% of breast cancers do not express the estrogen receptor-α (ERα) and consequently do not respond to endocrine therapy. In these tumors, ERα repression is often due to epigenetic modifications such as methylation and histone deacetylation. For this reason, we investigated the ability of the histone deacetylase inhibitor entinostat (ENT) to trigger reexpression of ERα and aromatase in breast cancer cells, with the notion that this treatment would restore sensitivity to the aromatase inhibitor (AI) letrozole. ENT treatment of tumor cells increased expression of ERα and aromatase, along with the enzymatic activity of aromatase, in a dose-dependent manner both in vitro and in vivo. Notably, ERα and aromatase upregulation resulted in sensitization of breast cancer cells to estrogen and letrozole. Tumor growth rate was significantly lower in tumor xenografts following treatment with ENT alone and in combination with letrozole than in control tumors (P > 0.001). ENT plus letrozole also prevented lung colonization and growth of tumor cells, with a significant reduction (P > 0.03) in both visible and microscopic foci. Our results show that ENT treatment can be used to restore the letrozole responsiveness of ER-negative tumors. More generally, they provide a strong rationale for immediate clinical evaluation of combinations of histone deacetylase and aromatase inhibitors to treat ER-negative and endocrine-resistant breast cancers.
AuthorsGauri J Sabnis, Olga Goloubeva, Saranya Chumsri, Nguyen Nguyen, Saraswati Sukumar, Angela M H Brodie
JournalCancer research (Cancer Res) Vol. 71 Issue 5 Pg. 1893-903 (Mar 1 2011) ISSN: 1538-7445 [Electronic] United States
PMID21245100 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright©2011 AACR.
Chemical References
  • Antineoplastic Agents
  • Benzamides
  • Estrogen Receptor alpha
  • Nitriles
  • Pyridines
  • Triazoles
  • entinostat
  • letrozole
  • Aromatase
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Aromatase (biosynthesis, drug effects)
  • Benzamides (pharmacology)
  • Blotting, Western
  • Estrogen Receptor alpha (biosynthesis, drug effects)
  • Female
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Nitriles (pharmacology)
  • Oligonucleotide Array Sequence Analysis
  • Pyridines (pharmacology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triazoles (pharmacology)
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: