Scriptaid effects on breast cancer cell lines.
In breast cancer tumor expression of estrogen receptors (ERs) is important as a marker of prognosis and mostly as a predictor of response to endocrine therapy. In fact, the loss of α-ER expression leads to unresponsiveness to anti-hormone treatment. In a significant fraction of breast cancers, this loss of expression is a result of epigenetic mechanisms, such as DNA methylation and histone deacetylation, within the α-ER promoter. Previous studies have shown that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), results in expression of functional α-ER mRNA and protein. Moreover, the activity of a novel HDAC inhibitor, Scriptaid, has been shown to induce inhibition of tumor growth in breast cancer and to cause re-expression of functional α-ER in α-ER negative breast cancer cells. We sought to better characterize the effects of Scriptaid on cell growth, apoptosis, and α-ER expression in α-ER-positive (MCF-7), α-ER-negative (MDA-MB-231), and α-ER-negative/Her-2 over-expressing (SKBr-3) human breast cancer cell lines. In all of these cell lines Scriptaid treatment resulted in significant growth inhibition and apoptosis, and RT-PCR confirmed an increase of α-ER mRNA transcript in MDA-MB-231 after 48 h of Scriptaid treatment. Furthermore, following treatment with Scriptaid, the formerly unresponsive MDA-MB-231 and SKBr-3 breast cancer cells became responsive to tamoxifen. These results show that the HDAC inhibitor Scriptaid is able to sensitize tamoxifen hormone-resistant breast cancer cells, and that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA. lauragiacinti@yahoo.it
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Giacinti
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Giacinti
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Gabellini
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Rizzuto
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Lopez
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Giordano
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines; D016328:NF-kappa B; D011804:Quinolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human; C410733:scriptaid; C508053:ERBB2 protein, human