Skip Navigation



Carcinogenesis Advance Access published online on May 5, 2005
Carcinogenesis, doi:10.1093/carcin/bgi113
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
26/9/1527    most recent
bgi113v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Bouker, K. B.
Right arrow Articles by Clarke, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bouker, K. B.
Right arrow Articles by Clarke, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received February 28, 2005
Revised April 14, 2005
Accepted April 26, 2005

CANCER BIOLOGY

Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis

Kerrie B. Bouker 1, Todd C. Skaar 2, Rebecca B. Riggins 1, David S. Harburger 1, David R. Fernandez 1, Alan Zwart 1, Antai Wang 3, and Robert Clarke 1*

1 Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University School of Medicine, 3970 Reservoir Rd NW, Washington, DC 20057
2 Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University School of Medicine, 3970 Reservoir Rd NW, Washington, DC 20057; Lombardi Comprehensive Cancer Center and Department of Medicine, Division of Clinical Pharmacology and Indiana University Cancer Center, Indiana University, Indianapolis, IN 46202, USA
3 Lombardi Comprehensive Cancer Center and Department of Biostatistics & Biomathematics, Georgetown University School of Medicine, 3970 Reservoir Rd NW, Washington, DC 20057

* To whom correspondence should be addressed.
Robert Clarke, E-mail: clarker{at}georgetown.edu


  Abstract

We have directly assessed the ability of Interferon Regulatory Factor-1 (IRF-1) to act as a tumor suppressor gene in human breast cancer cells and explored whether this suppressor function is mechanistically conferred by affecting cell cycle transition, apoptosis, and/or caspase activation. We have used a dual approach, measuring whether overexpression of wild type IRF-1 or a dominant negative IRF-1 (dnIRF-1) produce opposing effects on breast cancer cell proliferation in vitro or tumorigenicity in athymic nude mice. Mechanistic studies determined the effects of blocking endogenous IRF-1 expression on cell cycle transition by flow cytometry, on apoptosis by Annexin V staining, and on caspase activation by fluorescent substrate cleavage. IRF-1 mRNA (p≤0.001) and protein (p≤0.001) are highly expressed in non-tumorigenic, normal, mammary epithelial cells, with intermediate expression in tumorigenic but non-metastatic cells and very low expression in metastatic cell lines. In MCF-7 cells transfected with a wild type IRF-1 (MCF-7/IRF-1), IRF-1 mRNA expression inversely correlates with the rate of cell proliferation (r=-0.91; p=0.002). Conversely, expression of dnIRF-1 in both MCF-7 (MCF-7/dnIRF-1; p53 wild type) and T47D cells (T47D/dnIRF-1; p53 mutant) increases cell proliferation (p≤0.001). In athymic nude mice, the incidence of MCF-7/IRF-1 xenografts is reduced (p=0.045), whereas MCF-7/dnIRF-1 xenografts exhibit a significantly higher tumor incidence (p≤0.001). Effects of IRF-1/dnIRF-1 are mediated through changes in the rates of apoptosis and not through cell cycle regulation. MCF-7/dnIRF-1 cells exhibit a 50% decrease in basal apoptosis (p=0.007) and a significant reduction in caspase-8 activity (p=0.03); similar effects occur in T47D/dnIRF-1 cells, where the effects on apoptosis appear to be mediated through inhibition of caspase-3/7 (p<0.001) and caspase-8 (p=0.03). These data establish a functional role for IRF-1 in the growth suppression of breast cancer cells and strongly implicate IRF-1 as a tumor suppressor gene in breast cancer that acts, independent of p53, to control apoptosis.

Keywords: Interferon regulatory factor-1; IRF-1; tumor suppressor gene; cell cycle; proliferation; apoptosis; breast cancer.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Genes Dev.Home page
S. V. Sharma and J. Settleman
Oncogene addiction: setting the stage for molecularly targeted cancer therapy
Genes & Dev., December 15, 2007; 21(24): 3214 - 3231.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
B. P. Gomez, R. B. Riggins, A. N. Shajahan, U. Klimach, A. Wang, A. C. Crawford, Y. Zhu, A. Zwart, M. Wang, and R. Clarke
Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines
FASEB J, December 1, 2007; 21(14): 4013 - 4027.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Magnusson, R. Ehrnstrom, J. Olsen, and A. Sjolander
An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation
Cancer Res., October 1, 2007; 67(19): 9190 - 9198.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. Kroger, A. Stirnweiss, J. E. Pulverer, K. Klages, M. Grashoff, J. Reimann, and H. Hauser
Tumor Suppression by IFN Regulatory Factor-1 Is Mediated by Transcriptional Down-regulation of Cyclin D1
Cancer Res., April 1, 2007; 67(7): 2972 - 2981.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
A. J Lengi, R. A Phillips, E. Karpuzoglu, and S. A. Ahmed
17{beta}-Estradiol downregulates interferon regulatory factor-1 in murine splenocytes
J. Mol. Endocrinol., December 1, 2006; 37(3): 421 - 432.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Chen, M. Dokmanovic, W. D. Stein, R. J. Ardecky, and I. B. Roninson
Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-like Growth Arrest in MCF-7 Breast Carcinoma Cells.
Cancer Res., September 1, 2006; 66(17): 8749 - 8761.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
X. M. Luo and A. C. Ross
Retinoic Acid Exerts Dual Regulatory Actions on the Expression and Nuclear Localization of Interferon Regulatory Factor-1.
Experimental Biology and Medicine, May 1, 2006; 231(5): 619 - 631.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.