@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 {241, title = {Rapid disorganization of mechanically interacting systems of mammary acini.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Jan 14}, pages = {658-63}, abstract = {

Cells and multicellular structures can mechanically align and concentrate fibers in their ECM environment and can sense and respond to mechanical cues by differentiating, branching, or disorganizing. Here we show that mammary acini with compromised structural integrity can interconnect by forming long collagen lines. These collagen lines then coordinate and accelerate transition to an invasive phenotype. Interacting acini begin to disorganize within 12.5 \± 4.7 h in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize more slowly (in 21.8 \± 4.1 h) and to a lesser extent (P \< 0.0001). When the directed mechanical connections between acini were cut with a laser, the acini reverted to a slowly disorganizing phenotype. When acini were fully mechanically isolated from other acini and also from the bulk gel by box-cuts with a side length \<900 μm, transition to an invasive phenotype was blocked in 20 of 20 experiments, regardless of waiting time. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix, and these directed mechanical interactions facilitate transition to an invasive phenotype.

}, keywords = {Acinar Cells, Breast Neoplasms, Cell Communication, Cell Line, Tumor, Cell Separation, Collagen, Escherichia coli, Female, Humans, Kaplan-Meier Estimate, Mammary Glands, Human, Microscopy, Atomic Force, Microscopy, Electron, Scanning, Microscopy, Fluorescence}, issn = {1091-6490}, doi = {10.1073/pnas.1311312110}, author = {Shi, Quanming and Ghosh, Rajarshi P and Engelke, Hanna and Rycroft, Chris H and Cassereau, Luke and Sethian, James A and Weaver, Valerie M and Liphardt, Jan T} } @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 {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 {246, title = {Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas.}, journal = {Cancer Res}, volume = {73}, year = {2013}, month = {2013 Sep 1}, pages = {5336-46}, abstract = {

The tumor stromal environment can dictate many aspects of tumor progression. A complete understanding of factors driving stromal activation and their role in tumor metastasis is critical to furthering research with the goal of therapeutic intervention. Polyoma middle T-induced mammary carcinomas lacking the type II TGF-β receptor (PyMT(mgko)) are highly metastatic compared with control PyMT-induced carcinomas (PyMT(fl/fl)). We hypothesized that the PyMT(mgko)-activated stroma interacts with carcinoma cells to promote invasion and metastasis. We show that the extracellular matrix associated with PyMT(mgko) tumors is stiffer and has more fibrillar collagen and increased expression of the collagen crosslinking enzyme lysyl oxidase (LOX) compared with PyMT(fl/fl) mammary carcinomas. Inhibition of LOX activity in PyMT(mgko) mice had no effect on tumor latency and size, but significantly decreased tumor metastasis through inhibition of tumor cell intravasation. This phenotype was associated with a decrease in keratin 14-positive myoepithelial cells in PyMT(mgko) tumors following LOX inhibition as well as a decrease in focal adhesion formation. Interestingly, the primary source of LOX was found to be activated fibroblasts. LOX expression in these fibroblasts can be driven by myeloid cell-derived TGF-β, which is significantly linked to human breast cancer. Overall, stromal expansion in PyMT(mgko) tumors is likely caused through the modulation of immune cell infiltrates to promote fibroblast activation. This feeds back to the epithelium to promote metastasis by modulating phenotypic characteristics of basal cells. Our data indicate that epithelial induction of microenvironmental changes can play a significant role in tumorigenesis and attenuating these changes can inhibit metastasis. Cancer Res; 73(17); 5336-46. \©2013 AACR.

}, keywords = {Animals, Carcinogenesis, Collagen, Enzyme Inhibitors, Female, Fibroblasts, Focal Adhesion Kinase 1, Humans, In Situ Hybridization, Keratin-14, Lung Neoplasms, Mammary Neoplasms, Experimental, Mice, Mice, Transgenic, Microscopy, Atomic Force, Myeloid Cells, Phosphorylation, Protein-Lysine 6-Oxidase, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Signal Transduction, Stromal Cells, Transforming Growth Factor beta}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-0012}, author = {Pickup, Michael W and Laklai, Hanane and Acerbi, Irene and Owens, Philip and Gorska, Agnieszka E and Chytil, Anna and Aakre, Mary and Weaver, Valerie M and Moses, Harold L} } @article {351, title = {HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype.}, journal = {J Clin Invest}, volume = {120}, year = {2010}, month = {2010 May}, pages = {1535-50}, abstract = {

Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.

}, keywords = {Adult, Animals, BRCA1 Protein, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Mice, Middle Aged, Models, Genetic, Neoplasm Transplantation, Phenotype, Receptors, Estrogen, Receptors, Progesterone, Treatment Outcome}, issn = {1558-8238}, doi = {10.1172/JCI39534}, author = {Gilbert, Penney M and Mouw, Janna K and Unger, Meredith A and Lakins, Johnathon N and Gbegnon, Mawuse K and Clemmer, Virginia B and Benezra, Miriam and Licht, Jonathan D and Boudreau, Nancy J and Tsai, Kelvin K C and Welm, Alana L and Feldman, Michael D and Weber, Barbara L and Weaver, Valerie M} } @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 {371, title = {Filamin A-beta1 integrin complex tunes epithelial cell response to matrix tension.}, journal = {Mol Biol Cell}, volume = {20}, year = {2009}, month = {2009 Jul}, pages = {3224-38}, abstract = {

The physical properties of the extracellular matrix (ECM) regulate the behavior of several cell types; yet, mechanisms by which cells recognize and respond to changes in these properties are not clear. For example, breast epithelial cells undergo ductal morphogenesis only when cultured in a compliant collagen matrix, but not when the tension of the matrix is increased by loading collagen gels or by increasing collagen density. We report that the actin-binding protein filamin A (FLNa) is necessary for cells to contract collagen gels, and pull on collagen fibrils, which leads to collagen remodeling and morphogenesis in compliant, low-density gels. In stiffer, high-density gels, cells are not able to contract and remodel the matrix, and morphogenesis does not occur. However, increased FLNa-beta1 integrin interactions rescue gel contraction and remodeling in high-density gels, resulting in branching morphogenesis. These results suggest morphogenesis can be \"tuned\" by the balance between cell-generated contractility and opposing matrix stiffness. Our findings support a role for FLNa-beta1 integrin as a mechanosensitive complex that bidirectionally senses the tension of the matrix and, in turn, regulates cellular contractility and response to this matrix tension.

}, keywords = {Animals, Antigens, CD29, Biomechanical Phenomena, Cell Line, Tumor, Collagen, Contractile Proteins, Epithelial Cells, Extracellular Matrix, Filamins, Gels, Humans, Mice, Microfilament Proteins, Morphogenesis, Myosin Light Chains, Phosphorylation, Protein Binding}, issn = {1939-4586}, doi = {10.1091/mbc.E08-12-1186}, author = {Gehler, Scott and Baldassarre, Massimiliano and Lad, Yatish and Leight, Jennifer L and Wozniak, Michele A and Riching, Kristin M and Eliceiri, Kevin W and Weaver, Valerie M and Calderwood, David A and Keely, Patricia J} } @article {366, title = {Matrix crosslinking forces tumor progression by enhancing integrin signaling.}, journal = {Cell}, volume = {139}, year = {2009}, month = {2009 Nov 25}, pages = {891-906}, abstract = {

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.

}, keywords = {Aging, Animals, Breast Neoplasms, Collagen, Epidermal Growth Factor, Extracellular Matrix, Female, Fibrosis, Genes, ras, Humans, Integrins, Mammary Glands, Human, Mice, Mice, Inbred BALB C, Protein-Lysine 6-Oxidase, Signal Transduction}, issn = {1097-4172}, doi = {10.1016/j.cell.2009.10.027}, author = {Levental, Kandice R and Yu, Hongmei and Kass, Laura and Lakins, Johnathon N and Egeblad, Mikala and Erler, Janine T and Fong, Sheri F T and Csiszar, Katalin and Giaccia, Amato and Weninger, Wolfgang and Yamauchi, Mitsuo and Gasser, David L 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 {531, title = {beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.}, journal = {Cancer Cell}, volume = {2}, year = {2002}, month = {2002 Sep}, pages = {205-16}, abstract = {

Tumor cells can evade chemotherapy by acquiring resistance to apoptosis. We investigated the molecular mechanism whereby malignant and nonmalignant mammary epithelial cells become insensitive to apoptosis. We show that regardless of growth status, formation of polarized, three-dimensional structures driven by basement membrane confers protection to apoptosis in both nonmalignant and malignant mammary epithelial cells. By contrast, irrespective of their malignant status, nonpolarized structures are sensitive to induction of apoptosis. Resistance to apoptosis requires ligation of beta4 integrins, which regulates tissue polarity, hemidesmosome formation, and NFkappaB activation. Expression of beta4 integrin that lacks the hemidesmosome targeting domain interferes with tissue polarity and NFkappaB activation and permits apoptosis. These results indicate that integrin-induced polarity may drive tumor cell resistance to apoptosis-inducing agents via effects on NFkappaB.

}, keywords = {Apoptosis, Basement Membrane, Breast Neoplasms, Cell Polarity, Epithelial Cells, Extracellular Matrix, Female, Gene Expression Regulation, Neoplastic, Humans, Integrin beta4, NF-kappa B, Tumor Cells, Cultured}, issn = {1535-6108}, author = {Weaver, Valerie M and Leli{\`e}vre, Sophie and Lakins, Johnathon N and Chrenek, Micah A and Jones, Jonathan C R and Giancotti, Filippo and Werb, Zena and Bissell, Mina J} }