PMID- 19826415
OWN - NLM
STAT- MEDLINE
DCOM- 20100105
LR  - 20240312
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 28
IP  - 49
DP  - 2009 Dec 10
TI  - Matrix density-induced mechanoregulation of breast cell phenotype, signaling and 
      gene expression through a FAK-ERK linkage.
PG  - 4326-43
LID - 10.1038/onc.2009.299 [doi]
AB  - 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.
FAU - Provenzano, P P
AU  - Provenzano PP
AD  - Department of Pharmacology, University of Wisconsin, Madison, WI, USA. 
      ppproven@fhcrc.org
FAU - Inman, D R
AU  - Inman DR
FAU - Eliceiri, K W
AU  - Eliceiri KW
FAU - Keely, P J
AU  - Keely PJ
LA  - eng
GR  - CA076537/CA/NCI NIH HHS/United States
GR  - R01 CA114462/CA/NCI NIH HHS/United States
GR  - R01 EB000184-01/EB/NIBIB NIH HHS/United States
GR  - R01 CA142833/CA/NCI NIH HHS/United States
GR  - T32CA009681/CA/NCI NIH HHS/United States
GR  - R01 CA076537/CA/NCI NIH HHS/United States
GR  - R01 EB000184/EB/NIBIB NIH HHS/United States
GR  - R29 CA076537/CA/NCI NIH HHS/United States
GR  - T32 CA009681/CA/NCI NIH HHS/United States
GR  - T32 CA009681-11/CA/NCI NIH HHS/United States
GR  - R01 CA076537-07/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Breast Neoplasms/etiology/genetics/metabolism
MH  - Carcinoma/etiology/genetics/metabolism
MH  - Cell Count
MH  - Cell Proliferation
MH  - Cell Transformation, Neoplastic/genetics/metabolism
MH  - Cells, Cultured
MH  - Extracellular Matrix/chemistry/*physiology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism/*physiology
MH  - Female
MH  - Focal Adhesion Kinase 1/metabolism/*physiology
MH  - Gene Expression/physiology
MH  - Gene Expression Profiling
MH  - Humans
MH  - Mammary Glands, Human/*cytology/metabolism/physiology
MH  - Mechanotransduction, Cellular/genetics/*physiology
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phenotype
MH  - Risk Factors
PMC - PMC2795025
MID - NIHMS141653
COIS- CONFLICT OF INTEREST DISCLOSURE The authors declare no conflict of interest.
EDAT- 2009/10/15 06:00
MHDA- 2010/01/06 06:00
PMCR- 2010/06/10
CRDT- 2009/10/15 06:00
PHST- 2009/10/15 06:00 [entrez]
PHST- 2009/10/15 06:00 [pubmed]
PHST- 2010/01/06 06:00 [medline]
PHST- 2010/06/10 00:00 [pmc-release]
AID - onc2009299 [pii]
AID - 10.1038/onc.2009.299 [doi]
PST - ppublish
SO  - Oncogene. 2009 Dec 10;28(49):4326-43. doi: 10.1038/onc.2009.299.