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

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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.

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Acknowledgments

We thank Dr V Cavaillès, and Mrs C Brunin, E Wittmer, J Wang, A Pontisso, A Chomel, D Meseure, and C Laurent for their helpful contribution to this work. The study was supported by Servier Laboratories. However, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

Various co-authors, i.e., Gaëlle Rolland, Laurence Kraus-Berthier, Brian Paul Lockhar, and Stéphane Depil, are employees of Servier Laboratories which is developing abexinostat clinical therapeutic approach. The remaining authors declare that they have no competing interest.

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Authors and Affiliations

  1. APHP Hôpital Saint-Louis, Molecular Oncoloy Unit and University Paris-Diderot, PRES Paris Cité, INSERM/CNRS UMR944/7212, 1, Avenue Claude Vellefaux, 75010, Paris, France

    Patricia de Cremoux, Jacqueline Lehmann-Che & Hugues de Thé

  2. Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France

    Olivia N’Doye, Franck Assayag, Elisabetta Marangoni & Didier Decaudin

  3. LBME, University of Toulouse, Toulouse, France

    Mathieu Dalvai, Fatima Moutahir & Kerstin Bystricky

  4. UMR5099, CNRS, Toulouse, France

    Mathieu Dalvai & Fatima Moutahir

  5. Servier Laboratories, Suresnes, France

    Gaëlle Rolland, Laurence Kraus-Berthie, Brian Paul Lockhart & Stéphane Depil

  6. Department of Tumor Biology, Institut Curie, Paris, France

    Olfa Chouchane-Mlik & André Nicolas

  7. Department of Medical Oncology, Institut Curie, Paris, France

    Didier Decaudin

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  1. Patricia de Cremoux
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  2. Mathieu Dalvai
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  8. Jacqueline Lehmann-Che
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  11. Brian Paul Lockhart
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  12. Elisabetta Marangoni
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  13. Hugues de Thé
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  14. Stéphane Depil
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  16. Didier Decaudin
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Corresponding author

Correspondence to Patricia de Cremoux.

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de Cremoux, P., Dalvai, M., N’Doye, O. et al. HDAC inhibition does not induce estrogen receptor in human triple-negative breast cancer cell lines and patient-derived xenografts. Breast Cancer Res Treat 149, 81–89 (2015). https://doi.org/10.1007/s10549-014-3233-y

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  • DOI: https://doi.org/10.1007/s10549-014-3233-y

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