HDAC inhibition does not induce estrogen receptor in human triple-negative breast cancer cell lines and patient-derived xenografts

Breast Cancer Res Treat. 2015 Jan;149(1):81-9. doi: 10.1007/s10549-014-3233-y. Epub 2014 Dec 12.

Abstract

Several publications have suggested that histone deacetylase inhibitors (HDACis) could reverse the repression of estrogen receptor alpha (ERα) in triple-negative breast cancer (TNBC) cell lines, leading to the induction of a functional protein. Using different HDACis, vorinostat, panobinostat, and abexinostat, we therefore investigated this hypothesis in various human TNBC cell lines and patient-derived xenografts (PDXs). We used three human TNBC cell lines and three PDXs. We analyzed the in vitro toxicity of the compounds, their effects on the hormone receptors and hormone-related genes and protein expression both in vitro and in vivo models. We then explored intra-tumor histone H3 acetylation under abexinostat in xenograft models. Despite major cytotoxicity of all tested HDAC inhibitors and repression of deactylation-dependent CCND1 gene, neither ERα nor ERβ, ESR1 or ESR2 genes respectively, were re-expressed in vitro. In vivo, after administration of abexinostat for three consecutive days, we did not observe any induction of ESR1 or ESR1-related genes and ERα protein expression by RT-qPCR and immunohistochemical methods in PDXs. This observation was concomitant to the fact that in vivo administration of abexinostat increased intra-tumor histone H3 acetylation. These observations do not allow us to confirm previous studies which suggested that HDACis are able to convert ER-negative (ER-) tumors to ER-positive (ER+) tumors, and that a combination of HDAC inhibitors and hormone therapy could be proposed in the management of TNBC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzofurans / administration & dosage
  • Cell Proliferation / drug effects
  • Cyclin D1 / biosynthesis*
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor beta / antagonists & inhibitors
  • Estrogen Receptor beta / biosynthesis*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histones / genetics
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Indoles / administration & dosage
  • Panobinostat
  • Receptor, ErbB-2 / genetics
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology
  • Vorinostat
  • Xenograft Model Antitumor Assays

Substances

  • Benzofurans
  • CCND1 protein, human
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Indoles
  • Cyclin D1
  • Vorinostat
  • Panobinostat
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • abexinostat