Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells

N Fortunati; S Bertino; L Costantino; M De Bortoli; A Compagnone; A Bandino; M G Catalano; G Boccuzzi

doi:10.1016/j.mce.2009.09.011

Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells

Mol Cell Endocrinol. 2010 Jan 15;314(1):17-22. doi: 10.1016/j.mce.2009.09.011. Epub 2009 Sep 20.

Authors

N Fortunati¹, S Bertino, L Costantino, M De Bortoli, A Compagnone, A Bandino, M G Catalano, G Boccuzzi

Affiliation

¹ Oncological Endocrinology, AUO San Giovanni Battista, Torino, Italy.

PMID: 19772891
DOI: 10.1016/j.mce.2009.09.011

Abstract

Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ER alpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ER alpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ER alpha mRNA and protein, while did not modify ER beta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ER alpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Cell Line, Tumor / drug effects*
Cell Proliferation / drug effects
Enzyme Inhibitors / pharmacology*
Estradiol / metabolism
Estradiol / pharmacology
Estrogen Antagonists / pharmacology
Estrogen Receptor Modulators* / metabolism
Estrogen Receptor Modulators* / therapeutic use
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism*
Estrogen Receptor beta / genetics
Estrogen Receptor beta / metabolism
Female
Gene Expression Regulation, Neoplastic / drug effects
Hepatocyte Nuclear Factor 3-alpha / genetics
Hepatocyte Nuclear Factor 3-alpha / metabolism
Humans
Tamoxifen / pharmacology
Transcription, Genetic / drug effects
Valproic Acid / pharmacology*

Substances

Enzyme Inhibitors
Estrogen Antagonists
Estrogen Receptor Modulators
Estrogen Receptor alpha
Estrogen Receptor beta
FOXA1 protein, human
Hepatocyte Nuclear Factor 3-alpha
Tamoxifen
Estradiol
Valproic Acid