@article {721, title = {Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.}, journal = {Integr Biol (Camb)}, year = {2015}, month = {2015 May 11}, abstract = {

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.

}, issn = {1757-9708}, doi = {10.1039/c5ib00040h}, author = {Acerbi, I and Cassereau, L and Dean, I and Shi, Q and Au, A and Park, C and Chen, Y Y and Liphardt, J and Hwang, E S and Weaver, V M} } @article {731, title = {Tumor mechanics and metabolic dysfunction.}, journal = {Free Radic Biol Med}, volume = {79}, year = {2015}, month = {2015 Feb}, pages = {269-80}, abstract = {

Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.

}, issn = {1873-4596}, doi = {10.1016/j.freeradbiomed.2014.11.020}, author = {Tung, Jason C and Barnes, J Matthew and Desai, Shraddha R and Sistrunk, Christopher and Conklin, Matthew W and Schedin, Pepper and Eliceiri, Kevin W and Keely, Patricia J and Seewaldt, Victoria L and Weaver, Valerie M} } @article {671, title = {The cancer glycocalyx mechanically primes integrin-mediated growth and survival.}, journal = {Nature}, volume = {511}, year = {2014}, month = {2014 Jul 17}, pages = {319-25}, abstract = {

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.

}, keywords = {Animals, Breast, Cell Line, Tumor, Cell Proliferation, Cell Survival, Fibroblasts, Glycocalyx, Glycoproteins, Humans, Immobilized Proteins, Integrins, Mice, Molecular Targeted Therapy, Mucin-1, Neoplasm Metastasis, Neoplasms, Neoplastic Cells, Circulating, Protein Binding, Receptors, Cell Surface}, issn = {1476-4687}, doi = {10.1038/nature13535}, author = {Paszek, Matthew J and DuFort, Christopher C and Rossier, Olivier and Bainer, Russell and Mouw, Janna K and Godula, Kamil and Hudak, Jason E and Lakins, Jonathon N and Wijekoon, Amanda C and Cassereau, Luke and Rubashkin, Matthew G and Magbanua, Mark J and Thorn, Kurt S and Davidson, Michael W and Rugo, Hope S and Park, John W and Hammer, Daniel A and Giannone, Gr{\'e}gory and Bertozzi, Carolyn R and Weaver, Valerie M} } @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 = {

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."

}, 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 = {

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.

}, 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} } @article {266, title = {MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.}, journal = {Dev Cell}, volume = {25}, year = {2013}, month = {2013 May 28}, pages = {402-16}, abstract = {

In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct skeletal stem cell (SSC) commitment and differentiation. However, the mechanisms by which the SSC-ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remain unknown. Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis. By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a β1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment. These data identify a critical MT1-MMP/integrin/YAP/TAZ axis operative in the stem cell niche that oversees SSC fate determination.

}, keywords = {Adaptor Proteins, Signal Transducing, Adipogenesis, Animals, Antigens, CD29, Bone Marrow Cells, Cell Lineage, Cell Nucleus, Cell Shape, Cells, Cultured, Chondrogenesis, Extracellular Matrix, Gene Knock-In Techniques, Humans, Matrix Metalloproteinase 14, Mesenchymal Stromal Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteogenesis, Phenotype, Phosphoproteins, Proteolysis, Signal Transduction, Stem Cell Niche, Transcription Factors, Transcriptional Activation}, issn = {1878-1551}, doi = {10.1016/j.devcel.2013.04.011}, author = {Tang, Yi and Rowe, R Grant and Botvinick, Elliot L and Kurup, Abhishek and Putnam, Andrew J and Seiki, Motoharu and Weaver, Valerie M and Keller, Evan T and Goldstein, Steven and Dai, Jinlu and Begun, Dana and Saunders, Thomas and Weiss, Stephen J} } @article {256, title = {Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin.}, journal = {Oncogene}, year = {2013}, month = {2013 Jun 17}, abstract = {

Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBPβ expression to directly induce α5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBPβ-dependent α5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.Oncogene advance online publication, 17 June 2013; doi:10.1038/onc.2013.220.

}, issn = {1476-5594}, doi = {10.1038/onc.2013.220}, author = {Damiano, L and Stewart, K M and Cohet, N and Mouw, J K and Lakins, J N and Debnath, J and Reisman, D and Nickerson, J A and Imbalzano, A N and Weaver, V M} } @article {271, title = {A physical sciences network characterization of non-tumorigenic and metastatic cells.}, journal = {Sci Rep}, volume = {3}, year = {2013}, month = {2013}, pages = {1449}, abstract = {

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences-Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells\&$\#$39; regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.

}, keywords = {Cell Line, Tumor, Cell Movement, Cell Size, Cell Survival, Computer Simulation, Gene Expression Regulation, Neoplastic, Humans, Models, Biological, Neoplasm Metastasis, Neoplasm Proteins, Tumor Markers, Biological}, issn = {2045-2322}, doi = {10.1038/srep01449}, author = {Agus, David B and Alexander, Jenolyn F and Arap, Wadih and Ashili, Shashanka and Aslan, Joseph E and Austin, Robert H and Backman, Vadim and Bethel, Kelly J and Bonneau, Richard and Chen, Wei-Chiang and Chen-Tanyolac, Chira and Choi, Nathan C and Curley, Steven A and Dallas, Matthew and Damania, Dhwanil and Davies, Paul C W and Decuzzi, Paolo and Dickinson, Laura and Estevez-Salmeron, Luis and Estrella, Veronica and Ferrari, Mauro and Fischbach, Claudia and Foo, Jasmine and Fraley, Stephanie I and Frantz, Christian and Fuhrmann, Alexander and Gascard, Philippe and Gatenby, Robert A and Geng, Yue and Gerecht, Sharon and Gillies, Robert J and Godin, Biana and Grady, William M and Greenfield, Alex and Hemphill, Courtney and Hempstead, Barbara L and Hielscher, Abigail and Hillis, W Daniel and Holland, Eric C and Ibrahim-Hashim, Arig and Jacks, Tyler and Johnson, Roger H and Joo, Ahyoung and Katz, Jonathan E and Kelbauskas, Laimonas and Kesselman, Carl and King, Michael R and Konstantopoulos, Konstantinos and Kraning-Rush, Casey M and Kuhn, Peter and Kung, Kevin and Kwee, Brian and Lakins, Johnathon N and Lambert, Guillaume and Liao, David and Licht, Jonathan D and Liphardt, Jan T and Liu, Liyu and Lloyd, Mark C and Lyubimova, Anna and Mallick, Parag and Marko, John and McCarty, Owen J T and Meldrum, Deirdre R and Michor, Franziska and Mumenthaler, Shannon M and Nandakumar, Vivek and O{\textquoteright}Halloran, Thomas V and Oh, Steve and Pasqualini, Renata and Paszek, Matthew J and Philips, Kevin G and Poultney, Christopher S and Rana, Kuldeepsinh and Reinhart-King, Cynthia A and Ros, Robert and Semenza, Gregg L and Senechal, Patti and Shuler, Michael L and Srinivasan, Srimeenakshi and Staunton, Jack R and Stypula, Yolanda and Subramanian, Hariharan and Tlsty, Thea D and Tormoen, Garth W and Tseng, Yiider and van Oudenaarden, Alexander and Verbridge, Scott S and Wan, Jenny C and Weaver, Valerie M and Widom, Jonathan and Will, Christine and Wirtz, Denis and Wojtkowiak, Jonathan and Wu, Pei-Hsun} } @article {261, title = {YAP forces fibroblasts to feel the tension.}, journal = {Nat Cell Biol}, volume = {15}, year = {2013}, month = {2013 Jun}, pages = {570-2}, abstract = {

Cancer-associated fibroblasts (CAFs) may contribute to tissue tension and cancer progression by increasing extracellular matrix (ECM) deposition and remodelling. However, how CAFs become activated and their roles in tumour mechanics have remained unclear. YAP is now identified as a tension-stimulated CAF activator that promotes malignancy through a mechanically reinforced feed-forward loop.

}, keywords = {Adaptor Proteins, Signal Transducing, Animals, Breast Neoplasms, Female, Fibroblasts, Humans, Mechanotransduction, Cellular, Phosphoproteins}, issn = {1476-4679}, doi = {10.1038/ncb2777}, author = {Maller, Ori and DuFort, Christopher C and Weaver, Valerie M} } @article {286, title = {Morphogenesis: Laying down the tracks.}, journal = {Nat Mater}, volume = {11}, year = {2012}, month = {2012 Jun}, pages = {490-2}, keywords = {Cell Movement, Collagen, Epithelium, Extracellular Matrix, Feedback, Morphogenesis}, issn = {1476-1122}, doi = {10.1038/nmat3345}, author = {Cassereau, Luke and DuFort, Christopher C and Weaver, Valerie M} } @article {231, title = {Scanning angle interference microscopy reveals cell dynamics at the nanoscale.}, journal = {Nat Methods}, volume = {9}, year = {2012}, month = {2012 Aug}, pages = {825-7}, abstract = {

Emerging questions in cell biology necessitate nanoscale imaging in live cells. Here we present scanning angle interference microscopy, which is capable of localizing fluorescent objects with nanoscale precision along the optical axis in motile cellular structures. We use this approach to resolve nanotopographical features of the cell membrane and cytoskeleton as well as the temporal evolution, three-dimensional architecture and nanoscale dynamics of focal adhesion complexes.

}, keywords = {Cell Membrane, Cells, Cultured, Cytoskeleton, Epithelial Cells, Fibronectins, Focal Adhesions, Humans, Microscopy, Interference, Nanotechnology}, issn = {1548-7105}, doi = {10.1038/nmeth.2077}, author = {Paszek, Matthew J and DuFort, Christopher C and Rubashkin, Matthew G and Davidson, Michael W and Thorn, Kurt S and Liphardt, Jan T and Weaver, Valerie M} } @article {316, title = {Balancing forces: architectural control of mechanotransduction.}, journal = {Nat Rev Mol Cell Biol}, volume = {12}, year = {2011}, month = {2011 May}, pages = {308-19}, abstract = {

All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

}, keywords = {Animals, Cell Adhesion, Extracellular Matrix, Homeostasis, Humans, Intercellular Junctions, Mechanotransduction, Cellular, Models, Biological, Stress, Mechanical}, issn = {1471-0080}, doi = {10.1038/nrm3112}, author = {DuFort, Christopher C and Paszek, Matthew J and Weaver, Valerie M} } @article {321, title = {Tumor microenvironment and progression.}, journal = {J Surg Oncol}, volume = {103}, year = {2011}, month = {2011 May 1}, pages = {468-74}, abstract = {

Tumor blood vessels are heterogeneous, of at least six distinct types, are induced primarily by vascular endothelial growth factor-A (VEGF-A), and provide a potentially useful therapeutic target. Breast cancer is characterized by changes in the microenvironment that result in altered tensional homeostasis. Also, breast cancers arise as the result of epigenetic as well as genetic changes. Tumor blood vessel pericytes result, in part, from bone marrow precursor cells, and VEGF is a negative regulator of glioblastoma tumor cell invasion.

}, keywords = {Angiogenesis Inhibitors, Breast Neoplasms, Disease Progression, Female, Humans, Molecular Targeted Therapy, Neoplasm Invasiveness, Neoplasms, Neovascularization, Pathologic, Tumor Microenvironment, Vascular Endothelial Growth Factor A}, issn = {1096-9098}, doi = {10.1002/jso.21709}, author = {Dvorak, Harold F and Weaver, Valerie M and Tlsty, Thea D and Bergers, Gabriele} } @article {381, title = {CpG island tumor suppressor promoter methylation in non-BRCA-associated early mammary carcinogenesis.}, journal = {Cancer Epidemiol Biomarkers Prev}, volume = {18}, year = {2009}, month = {2009 Mar}, pages = {901-14}, abstract = {

BACKGROUND: Only 5\% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known.

METHODS: CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic women at high risk for breast cancer. Promoter methylation targets included RARB (M3 and M4), ESR1, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1.

RESULTS: Although the overall frequency of CpG island promoter methylation events increased with age (P\<0.0001), no specific methylation event was associated with age. In contrast, CpG island methylation of RARB M4 (P=0.051), INK4a/ARF (P=0.042), HIN-1 (P=0.044), and PRA (P=0.032), as well as the overall frequency of methylation events (P=0.004), was associated with abnormal Masood cytology. The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing. Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had

CONCLUSIONS: This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.

}, keywords = {Biopsy, Fine-Needle, Breast Neoplasms, Chi-Square Distribution, CpG Islands, Cyclin-Dependent Kinase Inhibitor p16, Cytokines, DNA Methylation, Female, Genes, BRCA1, Genes, BRCA2, Genes, Tumor Suppressor, Humans, Mutation, Polymerase Chain Reaction, Premenopause, Promoter Regions, Genetic, Receptors, Progesterone, Receptors, Retinoic Acid, Risk, Risk Assessment, Statistics, Nonparametric, Tumor Suppressor Proteins}, issn = {1055-9965}, doi = {10.1158/1055-9965.EPI-08-0875}, author = {Vasilatos, Shauna N and Broadwater, Gloria and Barry, William T and Baker, Joseph C and Lem, Siya and Dietze, Eric C and Bean, Gregory R and Bryson, Andrew D and Pilie, Patrick G and Goldenberg, Vanessa and Skaar, David and Paisie, Carolyn and Torres-Hernandez, Alejandro and Grant, Tracey L and Wilke, Lee G and Ibarra-Drendall, Catherine and Ostrander, Julie H and D{\textquoteright}Amato, Nicholas C and Zalles, Carola and Jirtle, Randy and Weaver, Valerie M and Seewaldt, Victoria L} } @article {431, title = {Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis.}, journal = {Int J Biochem Cell Biol}, volume = {39}, year = {2007}, month = {2007}, pages = {1987-94}, abstract = {

Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation.

}, keywords = {Animals, Cell Lineage, Cell Transformation, Neoplastic, Epithelial Cells, Extracellular Matrix, Female, Humans, Mammary Glands, Human, Neoplasms}, issn = {1357-2725}, doi = {10.1016/j.biocel.2007.06.025}, author = {Kass, Laura and Erler, Janine T and Dembo, Micah and Weaver, Valerie M} } @article {421, title = {Tensional homeostasis and the malignant phenotype.}, journal = {Cancer Cell}, volume = {8}, year = {2005}, month = {2005 Sep}, pages = {241-54}, abstract = {

Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.

}, keywords = {3T3 Cells, Animals, Cell Line, Tumor, Cell Shape, Cytoskeleton, Homeostasis, Mice, Neoplasms, Phenotype, Stress, Mechanical, Stromal Cells}, issn = {1535-6108}, doi = {10.1016/j.ccr.2005.08.010}, author = {Paszek, Matthew J and Zahir, Nastaran and Johnson, Kandice R and Lakins, Johnathon N and Rozenberg, Gabriela I and Gefen, Amit and Reinhart-King, Cynthia A and Margulies, Susan S and Dembo, Micah and Boettiger, David and Hammer, Daniel A and Weaver, Valerie M} } @article {551, title = {Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology.}, journal = {Proc Natl Acad Sci U S A}, volume = {95}, year = {1998}, month = {1998 Dec 8}, pages = {14821-6}, abstract = {

Anchorage and growth factor independence are cardinal features of the transformed phenotype. Although it is logical that the two pathways must be coregulated in normal tissues to maintain homeostasis, this has not been demonstrated directly. We showed previously that down-modulation of beta1-integrin signaling reverted the malignant behavior of a human breast tumor cell line (T4-2) derived from phenotypically normal cells (HMT-3522) and led to growth arrest in a three-dimensional (3D) basement membrane assay in which the cells formed tissue-like acini (14). Here, we show that there is a bidirectional cross-modulation of beta1-integrin and epidermal growth factor receptor (EGFR) signaling via the mitogen-activated protein kinase (MAPK) pathway. The reciprocal modulation does not occur in monolayer (2D) cultures. Antibody-mediated inhibition of either of these receptors in the tumor cells, or inhibition of MAPK kinase, induced a concomitant down-regulation of both receptors, followed by growth-arrest and restoration of normal breast tissue morphogenesis. Cross-modulation and tissue morphogenesis were associated with attenuation of EGF-induced transient MAPK activation. To specifically test EGFR and beta1-integrin interdependency, EGFR was overexpressed in nonmalignant cells, leading to disruption of morphogenesis and a compensatory up-regulation of beta1-integrin expression, again only in 3D. Our results indicate that when breast cells are spatially organized as a result of contact with basement membrane, the signaling pathways become coupled and bidirectional. They further explain why breast cells fail to differentiate in monolayer cultures in which these events are mostly uncoupled. Moreover, in a subset of tumor cells in which these pathways are misregulated but functional, the cells could be \"normalized\" by manipulating either pathway.

}, keywords = {Antigens, CD29, Basement Membrane, Breast, Cell Line, Epithelial Cells, Female, Humans, Protein Binding, Protein Conformation, Receptor, Epidermal Growth Factor}, issn = {0027-8424}, author = {Wang, F and Weaver, V M and Petersen, O W and Larabell, C A and Dedhar, S and Briand, P and Lupu, R and Bissell, M J} } @article {561, title = {Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies.}, journal = {J Cell Biol}, volume = {137}, year = {1997}, month = {1997 Apr 7}, pages = {231-45}, abstract = {

In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory beta1-integrin antibody or its Fab fragments led to a striking morphological and functional reversion to a normal phenotype. A stimulatory beta1-integrin antibody proved to be ineffective. The newly formed reverted acini re-assembled a basement membrane and re-established E-cadherin-catenin complexes, and re-organized their cytoskeletons. At the same time they downregulated cyclin D1, upregulated p21(cip,wat-1), and stopped growing. Tumor cells treated with the same antibody and injected into nude mice had significantly reduced number and size of tumors in nude mice. The tissue distribution of other integrins was also normalized, suggesting the existence of intimate interactions between the different integrin pathways as well as adherens junctions. On the other hand, nonmalignant cells when treated with either alpha6 or beta4 function altering antibodies continued to grow, and had disorganized colony morphologies resembling the untreated tumor colonies. This shows a significant role of the alpha6/beta4 heterodimer in directing polarity and tissue structure. The observed phenotypes were reversible when the cells were disassociated and the antibodies removed. Our results illustrate that the extracellular matrix and its receptors dictate the phenotype of mammary epithelial cells, and thus in this model system the tissue phenotype is dominant over the cellular genotype.

}, keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD29, Basement Membrane, Binding, Competitive, Breast Neoplasms, Cell Division, Extracellular Matrix, Female, Fluorescent Antibody Technique, Genotype, Humans, Immunoglobulin Fab Fragments, Integrin beta4, Mice, Phenotype, Rats, Signal Transduction, Transformation, Genetic, Tumor Cells, Cultured}, issn = {0021-9525}, author = {Weaver, V M and Petersen, O W and Wang, F and Larabell, C A and Briand, P and Damsky, C and Bissell, M J} }