Matrix density-induced mechanoregulation of breast cell phenotype, signaling, and gene expression through a FAK-ERK linkage

By Paolo P. Provenzano, David Inman, Kevin W. Eliceiri, P. Keely. Oncogene, 2009

670 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Immunology and Allergy, Oncology

View Paper: https://www.semanticscholar.org/paper/10640aa73264f1f4c2ff54ac8a0ac8a3961732a4

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Citations in the corpus

Role of YAP/TAZ in mechanotransduction (2011, background): “Forthis,weperformedabioinformaticanalysisongenes differentiallyexpressedinmammaryepithelialcells(MEC)grownon ECMofhighversuslowstiffness 9 .”
Force Fluctuations within Focal Adhesions Mediate ECM-Rigidity Sensing to Guide Directed Cell Migration (2012, background): “It is thought that FAK activity, induced by integrin engagement of rigid ECM (Provenzano et al., 2009), promotes phosphorylation of paxillin on tyrosines 31 and 118 (Schneider et al.”
Integrins and extracellular matrix in mechanotransduction. (2010, background): “cancer cells in stiff 3D matrices show more aggressive behavior such as luminal filling, invasion, and epithelial-mesenchymal transition (EMT) (Levental et al. 2009; Provenzano et al. 2009).”
Mechanical compression drives cancer cells toward invasive phenotype (2011, result): “Our results are consistent with results from 3D cultures, where increased matrix density or stiffness has been shown to trigger malignant transformation (23, 47, 48).”
The physics of cancer: the role of physical interactions and mechanical forces in metastasis (2011, positive): “Collagen crosslinking enhances integrin signalling as well as the bundling of individual fibre”
Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression (2015, background): “For instance, mammary cells in a stiff matrix are more proliferative,(80) upregulating proliferation-associated genes like cyclin D1,(81) and human breast carcinoma cells show an upregulation of an entire set of genes related to proliferation.(82) In contrast, mammary cells within compliant matrices”
Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments (2023, background): “Pathologic ECM induces FAK and ERK signaling pathway activation to promote cell proliferation in breast cancer [157] and gastric cancer [158].”
Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions (2010, background): “In the absence of FAK, both cell types exhibit defects in proliferation in stiff matrices (Klein et al., 2009; Provenzano et al., 2009).”