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

Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor α (ERα) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ERα expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ERα mRNA and protein, while did not modify ERβ. 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 ERα and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive “phenotype”, restoring their sensitivity to antiestrogen therapy.