@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 {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} }