@article {641,
	title = {Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate.},
	journal = {Cancer Res},
	volume = {74},
	year = {2014},
	month = {2014 Sep 1},
	pages = {4597-611},
	abstract = {<p>Extracellular matrix (ECM) stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechanotransducer, in mammary epithelial tissue transformation and invasion. We found that ECM stiffness stabilizes the assembly of a vinculin-talin-actin scaffolding complex that facilitates PI3K-mediated phosphatidylinositol (3,4,5)-triphosphate phosphorylation. Using defined two- and three-dimensional matrices, a mouse model of mammary tumorigenesis with vinculin mutants, and a novel super resolution imaging approach, we established that ECM stiffness, per se, promotes the malignant progression of a mammary epithelium by activating and stabilizing vinculin and enhancing Akt signaling at focal adhesions. Our studies also revealed that vinculin strongly colocalizes with activated Akt at the invasive border of human breast tumors, where the ECM is stiffest, and we detected elevated mechanosignaling. Thus, ECM stiffness could induce tumor progression by promoting the assembly of signaling scaffolds, a conclusion underscored by the significant association we observed between highly expressed focal adhesion plaque proteins and malignant transformation across multiple types of solid cancer. See all articles in this Cancer Research section, "Physics in Cancer Research."</p>
},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-13-3698},
	author = {Rubashkin, Matthew G and Cassereau, Luke and Bainer, Russell and DuFort, Christopher C and Yui, Yoshihiro and Ou, Guanqing and Paszek, Matthew J and Davidson, Michael W and Chen, Yunn-Yi and Weaver, Valerie M}
}
@article {226,
	title = {Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.},
	journal = {Nat Med},
	year = {2014},
	month = {2014 Mar 16},
	abstract = {<p>Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.</p>
},
	issn = {1546-170X},
	doi = {10.1038/nm.3497},
	author = {Mouw, Janna K and Yui, Yoshihiro and Damiano, Laura and Bainer, Russell O and Lakins, Johnathon N and Acerbi, Irene and Ou, Guanqing and Wijekoon, Amanda C and Levental, Kandice R and Gilbert, Penney M and Hwang, E Shelley and Chen, Yunn-Yi and Weaver, Valerie M}
}
