Document Detail

Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by AluI restriction enzyme.
MedLine Citation:
PMID:  17456778     Owner:  NLM     Status:  MEDLINE    
The importance of microenvironment and context in regulation of tissue-specific genes is well established. DNA exposure to or the sequestration from nucleases detects differences in higher order chromatin structure in intact cells without disturbing cellular or tissue architecture. To investigate the relationship between chromatin organization and tumor phenotype, we used an established three-dimensional assay in which normal and malignant human breast cells can be easily distinguished by the morphology of the structures they make (acinus-like versus tumor-like, respectively). We show that these phenotypes can be distinguished also by sensitivity to AluI digestion in which the malignant cells resist digestion relative to nonmalignant cells. Treatment of T4-2 breast cancer cells in three-dimensional culture with cAMP analogs or a phosphatidylinositol 3-kinase inhibitor not only reverted their phenotype from nonpolar to polar acinar-like structures but also enhanced chromatin sensitivity to AluI. By using different cAMP analogs, we show that cAMP-induced phenotypic reversion, polarization, and shift in DNA organization act through a cAMP-dependent protein-kinase A-coupled signaling pathway. Importantly, inhibitory antibody to fibronectin produced the same effect. These experiments underscore the concept that modifying the tumor microenvironment can alter the organization of tumor cells and demonstrate that architecture and global chromatin organization are coupled and highly plastic.
Tone Sandal; Klara Valyi-Nagy; Virginia A Spencer; Robert Folberg; Mina J Bissell; Andrew J Maniotis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  170     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-04-25     Completed Date:  2007-06-26     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1739-49     Citation Subset:  AIM; IM    
Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., 130 CSN (MC 847), Chicago, IL 60612, USA.
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MeSH Terms
Breast Neoplasms / genetics*,  ultrastructure*
Cell Culture Techniques
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cyclic AMP
DNA Restriction Enzymes / metabolism
DNA, Neoplasm / genetics*
Epigenesis, Genetic*
Flow Cytometry
Fluorescent Antibody Technique
Microscopy, Confocal
Grant Support
Reg. No./Substance:
0/DNA, Neoplasm; 60-92-4/Cyclic AMP; EC 3.1.21.-/DNA Restriction Enzymes
Comment In:
Am J Pathol. 2007 Nov;171(5):1726-7; author reply 1727   [PMID:  17982134 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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