@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} } @article {546, title = {Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype.}, journal = {J Mammary Gland Biol Neoplasia}, volume = {3}, year = {1998}, month = {1998 Apr}, pages = {201-13}, abstract = {

Historically, the study of normal human breast function and breast disorders has been significantly impaired by limitations inherent to available model systems. Recent improvements in human breast epithelial cell lines and three-dimensional (3-D)3 culture systems have contributed to the development of in vitro model systems that recapitulate differentiated epithelial cell phenotypes with remarkable fidelity. Molecular characterization of these human breast cell models has demonstrated that normal breast epithelial cell behavior is determined in part by the precise interplay that exists between a cell and its surrounding microenvironment. Recent functional studies of integrins in a human model system provide evidence to support the idea that the structural stability afforded by integrin-mediated cell-extracellular matrix interactions is an important determinant of normal cellular behavior, and that alterations in tissue structure can give rise to tumorigenic progression.

}, keywords = {Breast, Breast Neoplasms, Cell Line, Epithelial Cells, Extracellular Matrix, Female, Humans, Integrins, Models, Biological}, issn = {1083-3021}, author = {Schmeichel, K L and Weaver, V M 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} } @article {566, title = {The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay.}, journal = {Biochem Cell Biol}, volume = {74}, year = {1996}, month = {1996}, pages = {833-51}, abstract = {

The extracellular matrix (ECM) is a dominant regulator of tissue development and homeostasis. \"Designer microenvironments\" in culture and in vivo model systems have shown that the ECM regulates growth, differentiation, and apoptosis in murine and human mammary epithelial cells (MEC) through a hierarchy of transcriptional events involving the intricate interplay between soluble and physical signaling pathways. Furthermore, these studies have shown that these pathways direct and in turn are influenced by the tissue structure. Tissue structure is directed by the cooperative interactions of the cell-cell and cell-ECM pathways and can be modified by stromal factors. Not surprisingly then, loss of tissue structure and alterations in ECM components are associated with the appearance and dissemination of breast tumors, and malignancy is associated with perturbations in cell adhesion, changes in adhesion molecules, and a stromal reaction. Several lines of evidence now support the contention that the pathogenesis of breast cancer is determined (at least in part) by the dynamic interplay between the ductal epithelial cells, the microenvironment, and the tissue structure (acini). Thus, to understand the mechanisms involved in carcinogenesis, the role of the microenvironment (ECM as well as the stromal cells) with respect to tissue structure should be considered and studied. Towards this goal, we have established a unique human MEC model of tumorigenesis, which in concert with a three-dimensional assay, recapitulates many of the genetic and morphological changes observed in breast in cancer in vivo. We are currently using this system to understand the role of the microenvironment and tissue structure in breast cancer progression.

}, keywords = {Animals, Breast Neoplasms, Cell Adhesion, Epithelium, Extracellular Matrix, Humans, Models, Biological, Tumor Cells, Cultured}, issn = {0829-8211}, author = {Weaver, V M and Fischer, A H and Peterson, O W and Bissell, M J} }