@article {276, title = {Molecular profiling of prostatic acinar morphogenesis identifies PDCD4 and KLF6 as tissue architecture-specific prognostic markers in prostate cancer.}, journal = {Am J Pathol}, volume = {182}, year = {2013}, month = {2013 Feb}, pages = {363-74}, abstract = {

Histopathological classification of human prostate cancer (PCA) relies on the morphological assessment of tissue specimens but has limited prognostic value. To address this deficiency, we performed comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. We then applied an acinar morphogenesis-specific gene profile to two independent cohorts of patients with PCA (total n = 79) and found that those with tumors expressing this profile, which we designated acini-like tumors, had a significantly lower risk of postoperative relapse compared with those tumors with a lower correlation (hazard ratio, 0.078; log-rank test P = 0.009). Multivariate analyses showed superior prognostic prediction performance using this classification system compared with clinical criteria and Gleason scores. We prioritized the genes in this profile and identified programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as critical regulators and surrogate markers of prostatic tissue architectures, which form a gene signature that robustly predicts clinical prognosis with a remarkable accuracy in several large series of PCA tumors (total n = 161; concordance index, 0.913 to 0.951). Thus, by exploiting the genomic program associated with prostate glandular differentiation, we identified acini-like PCA and related molecular markers that significantly enhance prognostic prediction of human PCA.

}, keywords = {Acinar Cells, Aged, Apoptosis Regulatory Proteins, Cell Differentiation, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Male, Middle Aged, Morphogenesis, Organ Specificity, Prognosis, Prostate, Prostatic Neoplasms, Proto-Oncogene Proteins, Recurrence, RNA-Binding Proteins, Tumor Markers, Biological}, issn = {1525-2191}, doi = {10.1016/j.ajpath.2012.10.024}, author = {Li, Chi-Rong and Su, Jimmy J-M and Wang, Wei-Yu and Lee, Michael T-L and Wang, Ting-Yun and Jiang, Kuan-Ying and Li, Chein-Feng and Hsu, Jong-Ming and Chen, Chi-Kuan and Chen, Marcelo and Jiang, Shih-Sheng and Weaver, Valerie M and Tsai, Kelvin K-C} } @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 {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 {411, title = {Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion.}, journal = {J Cell Sci}, volume = {121}, year = {2008}, month = {2008 Jan 15}, pages = {226-33}, abstract = {

Integrin-mediated adhesion to substratum is required for cyclin D1 induction in mesenchymal cells, but we show here that the induction of cyclin D1 persists despite blockade of ECM-integrin signaling in MCF10A mammary epithelial cells. E-cadherin-mediated cell-cell adhesion also supports cyclin D1 induction in these cells, and the combined inhibition of both E-cadherin and integrin adhesion is required to prevent the expression of cyclin D1 mRNA and protein. Our previous studies described a pro-proliferative effect of E-cadherin in MCF10A cells, mediated by Rac, and we now show that Rac is required for cyclin D1 mRNA induction by both E-cadherin and integrin engagement. The levels of p21Cip1 and p27Kip1, Cdk inhibitors that are also targets of integrin signaling, are not affected by E-cadherin-mediated cell-cell adhesion. Finally, we show that the increased expression of cyclin D1 mRNA associated with E-cadherin-dependent cell-cell adhesion is causally linked to an increased entry into S phase. Our results identify Rac signaling to cyclin D1 as a crucial pro-proliferative effect of E-cadherin-mediated cell-cell adhesion.

}, keywords = {Cadherins, Cell Adhesion, Cell Communication, Cell Line, Tumor, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Humans, Integrins, Models, Biological, rac GTP-Binding Proteins, Signal Transduction}, issn = {0021-9533}, doi = {10.1242/jcs.017012}, author = {Fournier, Alaina K and Campbell, Latoya E and Castagnino, Paola and Liu, Wendy F and Chung, Betty M and Weaver, Valerie M and Chen, Christopher S and Assoian, Richard K} } @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} } @article {541, title = {Tumour-stromal interactions. Integrins and cell adhesions as modulators of mammary cell survival and transformation.}, journal = {Breast Cancer Res}, volume = {3}, year = {2001}, month = {2001}, pages = {224-9}, abstract = {

Stromal-epithelial interactions modulate mammary epithelial cell (MEC) growth and apoptosis by influencing cell adhesion and tissue organization. Perturbations in the mammary stroma and cell adhesion characterize breast tumors and underlie the altered tissue organization, disrupted tissue homeostasis and enhanced survival phenotype of the disease. Apoptosis resistance likely arises during malignant transformation via genetic and epigenetic modification of cell adhesion pathways induced by a changing tissue microenvironment. Acquisition of adhesion-linked survival networks that enhance MEC viability in the absence of basement membrane interactions probably promote malignant transformation, and may render breast tumors sufficiently resistant to exogenous apoptotic stimuli to generate multidrug resistance.

}, keywords = {Apoptosis, Basement Membrane, Breast Neoplasms, Cell Adhesion Molecules, Cell Communication, Cell Differentiation, Cell Survival, Cell Transformation, Neoplastic, Drug Resistance, Multiple, Epithelial Cells, Female, Gene Expression Regulation, Neoplastic, Humans, Integrins, Stromal Cells}, issn = {1465-5411}, author = {Chrenek, M A and Wong, P and Weaver, V M} }