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. J. Cell. Physiol. 227: 3426–3433, 2012. © 2011 Wiley Periodicals, Inc.

[1]  A. Giordano,et al.  Critical choices for modeling breast cancer in transgenic mouse models , 2012, Journal of cellular physiology.

[2]  A. Giordano,et al.  The tumor suppressor role of CTCF , 2012, Journal of cellular physiology.

[3]  T. Ueda,et al.  A novel histone deacetylase inhibitor, Scriptaid, induces growth inhibition, cell cycle arrest and apoptosis in human endometrial cancer and ovarian cancer cells. , 2006, International journal of molecular medicine.

[4]  Adrian V. Lee,et al.  Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Rakesh Kumar,et al.  Steroid hormone receptor signaling in tumorigenesis , 2005, Journal of cellular biochemistry.

[6]  Maria Sjöberg,et al.  Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. , 2005, Molecular endocrinology.

[7]  N. Colburn,et al.  Histone Deacetylase Inhibition Down-Regulates Cyclin D1 Transcription by Inhibiting Nuclear Factor-κB/p65 DNA Binding , 2005, Molecular Cancer Research.

[8]  P. Marks.  The Mechanism of the Anti-Tumor Activity of the Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA) , 2004, Cell cycle.

[9]  M. Beckmann,et al.  Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer. , 2004, European journal of endocrinology.

[10]  E. Dees,et al.  The proteasome as a target for cancer therapy. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  H. Kawai,et al.  Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α , 2003, International journal of cancer.

[12]  Daniel Delorme,et al.  Novel hydroxamate and anilide derivatives as potent histone deacetylase inhibitors: synthesis and antiproliferative evaluation. , 2003, Current medicinal chemistry.

[13]  Dipali Sharma,et al.  A Novel Histone Deacetylase Inhibitor, Scriptaid, Enhances Expression of Functional Estrogen Receptor α (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine , 2003, Breast Cancer Research and Treatment.

[14]  Jorge A. Almenara,et al.  The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. , 2003, Cancer research.

[15]  J. Herman,et al.  Specific Inhibition of DNMT1 by Antisense Oligonucleotides Induces Re-expression of Estrogen Receptor a (ER) in ER-negative Human Breast Cancer Cell Lines , 2003, Cancer biology & therapy.

[16]  H. Iwase.  Molecular action of the estrogen receptor and hormone dependency in breast cancer , 2003, Breast cancer.

[17]  Daniel Delorme,et al.  Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. , 2003, Journal of medicinal chemistry.

[18]  E. Levin,et al.  Proximal Events in Signaling by Plasma Membrane Estrogen Receptors* , 2003, The Journal of Biological Chemistry.

[19]  Donald P. McDonnell,et al.  Connections and Regulation of the Human Estrogen Receptor , 2002, Science.

[20]  G. Bae,et al.  Activation of p21WAF1/Cip1 Transcription through Sp1 Sites by Histone Deacetylase Inhibitor Apicidin , 2001, The Journal of Biological Chemistry.

[21]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells , 2001 .

[22]  J. Herman,et al.  Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. , 2000, Cancer research.

[23]  Y. Higashi,et al.  Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. , 2000, Carcinogenesis.

[24]  H. W. Lee,et al.  Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. , 2000, Cancer research.

[25]  S. Kern,et al.  A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library. , 2000, Cancer research.

[26]  D. Cohen,et al.  Histone Deacetylase Inhibition Selectively Alters the Activity and Expression of Cell Cycle Proteins Leading to Specific Chromatin Acetylation and Antiproliferative Effects* , 1999, The Journal of Biological Chemistry.

[27]  A. Ferguson,et al.  Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression , 1998, Oncogene.

[28]  S. Weitzman,et al.  Mapping of ER gene CpG island methylation-specific polymerase chain reaction. , 1998, Cancer research.

[29]  Daniel Metzger,et al.  Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase , 1995, Science.

[30]  R. Weigel,et al.  Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma. , 1993, Cancer research.

[31]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[32]  A. Giordano,et al.  Promise and failure of targeted therapy in breast cancer. , 2012, Frontiers in bioscience.

[33]  A. Giordano,et al.  Epigenetic information and estrogen receptor alpha expression in breast cancer. , 2006, The oncologist.

[34]  N. Colburn,et al.  Histone Deacetylase Inhibition Down-Regulates Cyclin D 1 Transcription by Inhibiting Nuclear Factor-K B / p 65 DNA Binding , 2005 .

[35]  P. Marks,et al.  Histone deacetylase inhibitors: development as cancer therapy. , 2004, Novartis Foundation symposium.

[36]  S. Nass,et al.  The Loss of Estrogen and Progesterone Receptor Gene Expression in Human Breast Cancer , 2004, Journal of Mammary Gland Biology and Neoplasia.

[37]  S. Grant,et al.  The Histone Deacetylase Inhibitor MS-275 Promotes Differentiation or Apoptosis in Human Leukemia Cells through a Process Regulated by Generation of Reactive Oxygen Species and Induction of p 21 CIP 1 / WAF 1 1 , 2003 .

[38]  Vigushin Dm,et al.  Histone deacetylase inhibitors in cancer treatment. , 2002 .

[39]  D. Vigushin,et al.  Histone deacetylase inhibitors in cancer treatment. , 2002, Anti-cancer drugs.

[40]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. , 2001, Cancer research.

[41]  G. Bae,et al.  Activation of p 21 WAF 1 / Cip 1 Transcription through Sp 1 Sites by Histone Deacetylase Inhibitor Apicidin INVOLVEMENT OF PROTEIN KINASE , 2001 .

[42]  S. Weitzman,et al.  Mapping of ER gene CpG island methylation-specific polymerase chain reaction. , 1998, Cancer research.