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 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.
Fortunati
N
N
Oncological Endocrinology, AUO San Giovanni Battista, Torino, Italy.
Bertino
S
S
Costantino
L
L
De Bortoli
M
M
Compagnone
A
A
Bandino
A
A
Catalano
M G
MG
Boccuzzi
G
G
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D013629:Tamoxifen; D004958:Estradiol; D014635:Valproic Acid