HDAC Inhibitor Entinostat Restores Responsiveness of Letrozole-Resistant MCF-7Ca Xenografts to Aromatase Inhibitors through Modulation of Her-2

Sabnis, Gauri J.; Goloubeva, Olga G.; Kazi, Armina A.; Shah, Preeti; Brodie, Angela H.

doi:10.1158/1535-7163.mct-13-0345

Cited by 74Estrogen and related hormone effectsHistone Deacetylase Inhibitors ResearchBreast Cancer Treatment Studies

HDAC Inhibitor Entinostat Restores Responsiveness of Letrozole-Resistant MCF-7Ca Xenografts to Aromatase Inhibitors through Modulation of Her-2

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Sabnis, Gauri J., Goloubeva, Olga G., Kazi, Armina A., Shah, Preeti, Brodie, Angela H.·2013·Molecular Cancer Therapeutics

DOI 10.1158/1535-7163.mct-13-0345PMC PMC3858401

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Abstract

We previously showed that in innately resistant tumors, silencing of the estrogen receptor (ER) could be reversed by treatment with a histone deacetylase (HDAC) inhibitor, entinostat. Tumors were then responsive to aromatase inhibitor (AI) letrozole. Here, we investigated whether ER in the acquired letrozole-resistant tumors could be restored with entinostat. Ovariectomized athymic mice were inoculated with MCF-7Ca cells, supplemented with androstenedione (Δ4A), the aromatizable substrate. When the tumors reached about 300 mm3, the mice were treated with letrozole. After initial response to letrozole, the tumors eventually became resistant (doubled their initial volume). The mice then were grouped to receive letrozole, exemestane (250 μg/d), entinostat (50 μg/d), or the combination of entinostat with letrozole or exemestane for 26 weeks. The growth rates of tumors of mice treated with the combination of entinostat with letrozole or exemestane were significantly slower than with the single agent (P < 0.05). Analysis of the letrozole-resistant tumors showed entinostat increased ERα expression and aromatase activity but downregulated Her-2, p-Her-2, p-MAPK, and p-Akt. However, the mechanism of action of entinostat in reversing acquired resistance did not involve epigenetic silencing but rather included posttranslational as well as transcriptional modulation of Her-2. Entinostat treatment reduced the association of the Her-2 protein with HSP-90, possibly by reducing the stability of Her-2 protein. In addition, entinostat also reduced Her-2 mRNA levels and its stability. Our results suggest that the HDAC inhibitor may reverse letrozole resistance in cells and tumors by modulating Her-2 expression and activity. Mol Cancer Ther; 12(12); 2804–16. ©2013 AACR.

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Epigenetic modification alters gene expression leading to endocrine therapy resistance and may be reversed by epigenetic modifiers such as histone deacetylase (HDAC) inhibitors.
“Epigenetic modification alters gene expression leading to endocrine therapy resistance and may be reversed by epigenetic modifiers such as histone deacetylase (HDAC) inhibitors.6-8”
From E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor–Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group (2021) · cites this paper as [7]
Entinostat has overcome endocrine therapy resistance in letrozole-resistant mouse models.
“Entinostat has also overcome endocrine therapy resistance in letrozole-resistant mouse models.7”
From E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor–Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group (2021) · cites this paper as [7]

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[21]Sabnis GJ Goloubeva O Chumsri S Nguyen N Sukumar S Brodie AM Functional Activation of the Estrogen Receptor-alpha; and Aromatase by the HDAC Inhibitor Entinostat Sensitizes ER-Negative Tumors to Letrozole Cancer Res 2011 71 1893 903 21245100 PMC3076193

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Authors: Sabnis, G. J., Goloubeva, O. G., Kazi, A. A., Shah, P., & Brodie, A. H.
Affiliations: University of Maryland, Baltimore (US)
Corresponding author: Sabnis, Gauri J.
ORCID: Sabnis, Gauri J.
Venue: Molecular Cancer Therapeutics
Publisher: American Association for Cancer Research (AACR)
Published: 2013-12-01
Volume: 12
Issue: 12
Pages: 2804-2816
ISSN: 1535-7163 (ISSN-L)
1538-8514
DOI: 10.1158/1535-7163.mct-13-0345
PMC: PMC3858401
OpenAlex: W2103268736
Cited by: 74
References: 39
Citations by year: 2026: 8 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 11 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 5 · 2013: 2
FWCI: 4.42
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Cancer Therapeutics (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Susan G. Komen
Syndax Pharmaceuticals
National Institutes of Health
National Cancer Institute (CA62483, R01CA062483)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords: entinostat, histone deacetylase inhibitors, letrozole resistance, aromatase inhibitors, HER2, estrogen receptor alpha, acquired drug resistance, HSP90, protein stability, MAPK signaling, Akt signaling, exemestane, breast cancer
MeSH terms: Letrozole, Animals, Antineoplastic Agents, Aromatase, Benzamides, Disease Models, Animal, Female, Humans, Nitriles, Pyridines, Triazoles, Gene Expression Regulation, Neoplastic, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, HSP90 Heat-Shock Proteins, Drug Resistance, Neoplasm, RNA Stability, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Aromatase Inhibitors, Tumor Burden, Estrogen Receptor alpha, Mice, Histone Deacetylase Inhibitors, MCF-7 Cells

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HDAC Inhibitor Entinostat Restores Responsiveness of Letrozole-Resistant MCF-7Ca Xenografts to Aromatase Inhibitors through Modulation of Her-2

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