@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 {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 {356, title = {SWI/SNF chromatin remodeling enzyme ATPases promote cell proliferation in normal mammary epithelial cells.}, journal = {J Cell Physiol}, volume = {223}, year = {2010}, month = {2010 Jun}, pages = {667-78}, abstract = {

The ATPase subunits of the SWI/SNF chromatin remodeling enzymes, Brahma (BRM) and Brahma-related gene 1 (BRG1), can induce cell cycle arrest in BRM and BRG1 deficient tumor cell lines, and mice heterozygous for Brg1 are pre-disposed to breast tumors, implicating loss of BRG1 as a mechanism for unregulated cell proliferation. To test the hypothesis that loss of BRG1 can contribute to breast cancer, we utilized RNA interference to reduce the amounts of BRM or BRG1 protein in the nonmalignant mammary epithelial cell line, MCF-10A. When grown in reconstituted basement membrane (rBM), these cells develop into acini that resemble the lobes of normal breast tissue. Contrary to expectations, knockdown of either BRM or BRG1 resulted in an inhibition of cell proliferation in monolayer cultures. This inhibition was strikingly enhanced in three-dimensional rBM culture, although some BRM-depleted cells were later able to resume proliferation. Cells did not arrest in any specific stage of the cell cycle; instead, the cell cycle length increased by approximately 50\%. Thus, SWI/SNF ATPases promote cell cycle progression in nonmalignant mammary epithelial cells.

}, keywords = {Adenosine Triphosphatases, Basement Membrane, Cell Cycle, Cell Line, Cell Proliferation, Chromatin Assembly and Disassembly, DNA Helicases, Doxycycline, Epithelial Cells, Female, Gene Knockdown Techniques, Humans, Mammary Glands, Human, Nuclear Proteins, Protein Subunits, RNA, Small Interfering, RNA, Small Nucleolar, Transcription Factors, Up-Regulation}, issn = {1097-4652}, doi = {10.1002/jcp.22072}, author = {Cohet, Nathalie and Stewart, Kathleen M and Mudhasani, Rajini and Asirvatham, Ananthi J and Mallappa, Chandrashekara and Imbalzano, Karen M and Weaver, Valerie M and Imbalzano, Anthony N and Nickerson, Jeffrey A} }