| Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. | |
| | |
MedLine Citation:
|
PMID: 19826415 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma, yet the associated molecular mechanisms remain largely unknown. Importantly, regions of high breast density are associated with increased stromal collagen and epithelial cell content. We set out to determine whether increased collagen-matrix density, in the absence of stromal cells, was sufficient to promote proliferation and invasion characteristic of a malignant phenotype in non-transformed mammary epithelial cells. We demonstrate that increased collagen-matrix density increases matrix stiffness to promote an invasive phenotype. High matrix stiffness resulted in increased formation of activated three-dimensional (3D)-matrix adhesions and a chronically elevated outside-in/inside-out focal adhesion (FA) kinase (FAK)-Rho signaling loop, which was necessary to generate and maintain the invasive phenotype. Moreover, this signaling network resulted in hyperactivation of the Ras-mitogen-activated protein kinase (MAPK) pathway, which promoted growth of mammary epithelial cells in vitro and in vivo and activated a clinically relevant proliferation signature that predicts patient outcome. Hence, the current data provide compelling evidence for the importance of the mechanical features of the microenvironment, and suggest that mechanotransduction in these cells occurs through a FAK-Rho-ERK signaling network with extracellular signal-regulated kinase (ERK) as a bottleneck through which much of the response to mechanical stimuli is regulated. As such, we propose that increased matrix stiffness explains part of the mechanism behind increased epithelial proliferation and cancer risk in human patients with high breast tissue density. |
| | |
Authors:
|
P P Provenzano; D R Inman; K W Eliceiri; P J Keely |
Related Documents
:
|
16617165 - Novel alpha1-adrenergic receptor signaling pathways: secreted factors and interactions ... 9420605 - Hyperpolarisation of cultured human chondrocytes following cyclical pressure-induced st... 11342655 - Role of p190rhogap in beta 2 integrin regulation of rhoa in human neutrophils. 15630415 - Integrin-linked kinase: a cancer therapeutic target unique among its ilk. 20890305 - Regulation of mixed lineage kinase 3 is required for neurofibromatosis-2-mediated growt... 1453155 - Steroidogenesis in fundulus heteroclitus. iv. dichotomous effects of a phorbol ester on... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Oncogene Volume: 28 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2009 Dec |
Date Detail:
|
Created Date: 2009-12-16 Completed Date: 2010-01-05 Revised Date: 2011-08-22 |
Medline Journal Info:
|
Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
|
Languages: eng Pagination: 4326-43 Citation Subset: IM |
Affiliation:
|
Department of Pharmacology, University of Wisconsin, Madison, WI, USA. ppproven@fhcrc.org |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Breast Neoplasms
/
etiology,
genetics,
metabolism Carcinoma / etiology, genetics, metabolism Cell Count Cell Proliferation Cell Transformation, Neoplastic / genetics, metabolism Cells, Cultured Extracellular Matrix / chemistry, physiology* Extracellular Signal-Regulated MAP Kinases / metabolism, physiology* Female Focal Adhesion Kinase 1 / metabolism, physiology* Gene Expression / physiology Gene Expression Profiling Humans Mammary Glands, Human / cytology*, metabolism, physiology Mechanotransduction, Cellular / genetics, physiology* Oligonucleotide Array Sequence Analysis Phenotype Risk Factors |
| Grant Support | |
ID/Acronym/Agency:
|
CA076537/CA/NCI NIH HHS; R01 CA076537-07/CA/NCI NIH HHS; R01 EB000184-01/EB/NIBIB NIH HHS; T32 CA009681-11/CA/NCI NIH HHS; T32CA009681/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
EC 2.7.1.112/PTK2 protein, human; EC 2.7.10.1/Focal Adhesion Kinase 1; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Tumor suppressor U19/EAF2 regulates thrombospondin-1 expression via p53.
Next Document: The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppressi...