Document Detail

Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis.
MedLine Citation:
PMID:  15361828     Owner:  NLM     Status:  MEDLINE    
The growth of human breast tumor cells is regulated through signaling involving cell surface growth factor receptors and nuclear receptors of the steroid/thyroid/retinoid receptor gene family. Retinoic acid receptors (RARs), members of the steroid/thyroid hormone receptor gene family, are ligand-dependent transcription factors, which have in vitro and in vivo growth inhibitory activity against breast cancer cells. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. Additionally, RAR-agonists and synthetic retinoids such as Ferentinide have been shown to induce apoptosis in malignant breast cells but not normal breast cells. To better define the genes involved in RAR-mediated growth inhibition of breast cancer cells, we used oligonucleotide microarray analysis to create a database of genes that are potentially regulated by RAR-agonists in breast cancer cells. We found that PDCD4 (programmed cell death 4), a tumor suppressor gene presently being evaluated as a target for chemoprevention, was induced about three-fold by the RARalpha-selective agonist Am580, in T-47D breast cancer cells. RAR pan-agonists and Am580, but not retinoid X receptors (RXR)-agonists, stimulate the expression of PDCD4 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not induce PDCD4 expression in breast cancer cell lines, which were not growth inhibited by retinoids. We also observed that antiestrogen and the HER-2/neu antagonist, Herceptin (Trastuzumab), also induced PDCD4 expression in T-47D cells, suggesting that PDCD4 may play a central role in growth inhibition in breast cancer cells. Transient overexpression of PDCD4 in T-47D (ER+, RAR+) and MDA-MB-231 (ER-, RAR-) cells resulted in apoptotic death, suggesting a role for PDCD4 in mediating apoptosis in breast cancer cells. PDCD4 protein expression has previously been reported in small ductal epithelium of normal breast. To date, there has been no report of induction of PDCD4 expression by RAR-agonists, antiestrogen or HER2/neu antagonist in breast cancer cells and its potential role in apoptosis in these cells.
Olubunmi Afonja; Dominique Juste; Sharmistha Das; Sachiko Matsuhashi; Herbert H Samuels
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Oncogene     Volume:  23     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-10-21     Completed Date:  2004-11-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  8135-45     Citation Subset:  IM    
Department of Pediatrics, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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MeSH Terms
Apoptosis Regulatory Proteins
Breast Neoplasms / genetics*,  pathology*
Cell Cycle
Cell Line, Tumor
Estrogen Antagonists / pharmacology*
Gene Expression Regulation, Neoplastic*
RNA-Binding Proteins / genetics*,  physiology
Receptor, erbB-2 / antagonists & inhibitors,  physiology*
Receptors, Retinoic Acid / agonists,  physiology*
Retinoid X Receptors
Transcription Factors / physiology
Grant Support
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Estrogen Antagonists; 0/PDCD4 protein, human; 0/RNA-Binding Proteins; 0/Receptors, Retinoic Acid; 0/Retinoid X Receptors; 0/Transcription Factors; EC, erbB-2

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