Document Detail


Mechanisms by which the extracellular matrix and integrin signaling act to regulate the switch between tumor suppression and tumor promotion.
MedLine Citation:
PMID:  21822945     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cell adhesion to the extracellular matrix (ECM) is necessary for development of the mammary gland, and to maintain the normal architecture and function of the gland. Cells adhere to the ECM via the integrin family of trans-membrane receptors, which signal to control mammary-specific gene expression and regulate cell proliferation and survival. During tumor formation, the ECM is extensively remodeled and signaling through integrins is altered such that cells become proliferative and invasive. A key regulator of whether integrin-mediated adhesion will promote tumor suppression or tumor formation is the stiffness of the stromal ECM. The normal mammary gland is typically surrounded by a loose collagenous stroma. An increase in the deposition of collagen and other stromal components is associated with mammographic density, which is one of the greatest risk factors for developing breast carcinoma. Several groups have demonstrated that increased stromal ECM density results in a matrix that is stiffer. Cells sense the stiffness of their surrounding ECM by Rho-mediated contraction of the actin-myosin cytoskeleton. If the surrounding ECM is stiffer than the cell's ability to contract it, then the tensile forces that result are able to drive the clustering of integrins and assemble adhesion signaling complexes. The result is subsequent activation of signaling pathways including FAK, ERK, and PI3K that drive cell proliferation and survival. In contrast, focal complexes are not formed in a compliant matrix, and activation of FAK and pERK is diminished, resulting in control of proliferation. Signaling from FAK moreover regulates p53 and miR-200 members, which control apoptosis and epithelial phenotype, such that a compliant matrix is predicted to promote normal mammary gland architecture and suppress tumor formation.
Authors:
Patricia J Keely
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Publication Detail:
Type:  Journal Article; Review     Date:  2011-08-07
Journal Detail:
Title:  Journal of mammary gland biology and neoplasia     Volume:  16     ISSN:  1573-7039     ISO Abbreviation:  J Mammary Gland Biol Neoplasia     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-15     Completed Date:  2012-02-07     Revised Date:  2014-01-16    
Medline Journal Info:
Nlm Unique ID:  9601804     Medline TA:  J Mammary Gland Biol Neoplasia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  205-19     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Breast Neoplasms / metabolism*,  pathology*
Extracellular Matrix / metabolism*
Female
Humans
Integrins / metabolism*
Mammary Glands, Human / metabolism*,  pathology*
Signal Transduction
Grant Support
ID/Acronym/Agency:
R01 CA114462/CA/NCI NIH HHS; R01 CA142833/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Integrins
Comments/Corrections

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


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