ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 OC6.9

The histone deacetylase inhibitor valproic acid (VPA) confers an estrogen-sensitive 'phenotype' to estrogen receptor-negative breast cancer cells MDA-MB 231

Nicoletta Fortunati2, Silvia Bertino1, Lucia Costantino1, Maria Graziella Catalano1 & Giuseppe Boccuzzi1

1Dipartimento di Fisiopatologia Clinica, Università di Torino, Torino, Italy; 2SCDU Endocrinologia Oncologica, ASO San Giovanni Battista, Torino, Italy.

Breast cancer cells may present a number of resistance mechanisms to conventional therapy, and therefore new treatments are under evaluation. The histone deacetylase inhibitor (HDI) valproic acid (VPA) is of particular interest, since having been used for a long time in neurological patients its side-effects and tolerability are well known. We have recently demonstrated that VPA is a powerful antiproliferative agent in estrogen-sensitive breast cancer cells. Unfortunately, its ability to arrest cell growth in estrogen-resistant breast cancer cells is poor. In the present study, we evaluated the effect of VPA on the expression of estrogen receptor alpha (ER alpha) and the estrogen-sensitivity of ER-negative breast cancer cells, MDA-MB 231. VPA induced the expression of ER alpha; VPA-treated cells were then exposed to 10 nM estradiol and some estrogen-regulated genes were evaluated with real time-PCR. After VPA treatment, estradiol up-regulated progesterone receptor (PR), pS2, and AREG, and down-regulated ER alpha itself, giving to MDA-MB 231 cells a behaviour similar to that of estrogen-sensitive cells. In order to clarify that the ER alpha induced by VPA in these cells was a fully functioning receptor, a transcription assay using as reporter the luciferase gene was performed. MDA-MB 231 cells, transfected with ERE-tk-LUC, were first treated with VPA and then exposed to estradiol, before evaluating luciferase activity. While in MDA-MB 231 cells in basal condition estradiol was not able to stimulate any luciferae activity, the answer of VPA-treated cells to estradiol was similar to that of estrogen-sensitive cells. In conclusion, the HDI VPA is able to induce ER alpha expression in ER-negative cells, giving them a completely estrogen-sensitive ‘phenotype’. The possibility to restore estrogen-sensitivity in ER-negative breast cancer cells thus open up the chance to use anti-estrogen therapy even in this tumour type.

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