Integrin signaling in mammary epithelial cells and breast cancer (original) (raw)
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Integrins in Mammary Gland Development and Differentiation of Mammary Epithelium
Journal of Mammary Gland Biology and Neoplasia, 2000
Integrins are major extracellular matrix (ECM) receptors that can also serve for some cellcell interactions. They have been identified as important regulators of mammary epithelial cell growth and differentiation. Their ability to promote cell anchorage, proliferation, survival, migration, and the induction of active ECM-degrading enzymes suggests that they play an essential role in normal mammary morphogenesis, but, on the other hand, reveals their potential to promote tumor progression.
Breast Cancer Research, 2011
Consistent with their essential role in cell adhesion to the extracellular matrix, integrins and their associated signaling pathways have been shown to be involved in cell proliferation, migration, invasion and survival, processes required in both tumorigenesis and metastasis. β1-integrins represent the predominantly expressed integrins in mammary epithelial cells and have been proven crucial for mammary gland development and diff erentiation. Here we provide an overview of the studies that have used transgenic mouse models of mammary tumorigenesis to establish β1-integrin as a critical mediator of breast cancer progression and thereby as a potential therapeutic target for the development of new anticancer strategies.
Journal of mammary gland biology and neoplasia, 1998
The integrins are a family of cell surface adhesion receptors that mediate adhesion to either components of the extracellular matrix or to other cells. The beta1 family of integrins represent the major class of cell substrate receptors with specificities primarily for collagens, laminins, and fibronectins. The role of the integrin family of cell surface adhesion receptors in normal mammary gland morphogenesis and the contributions of altered integrin receptor expression to the invasive and metastatic phenotype have been the primary focus of our lab, as well as a number of other laboratories. The alpha2beta1 integrin is expressed at high levels by normal differentiated epithelial cells including those of the normal breast. Using breast cancer as a model, we evaluated changes in integrin expression in malignancy. We and other investigators made the key observation that alpha2beta1 integrin expression is decreased in adenocarcinoma of the breast in a manner that correlates with the sta...
Bi-Directional Signaling: Extracellular Matrix and Integrin Regulation of Breast Tumor Progression
Critical Reviews in Eukaryotic Gene Expression, 2013
Cell transformation and tumor progression involves a common set of acquired capabilities, including increased proliferation, failure of cell death, self-sufficiency in growth, angiogenesis, and tumor cell invasion and metastasis (1). The stromal environment consists of many cell types, including fibroblasts, macrophages, and endothelial cells, in addition to various extracellular matrix (ECM) proteins that function to support normal tissue maintenance, but have also been implicated in tumor progression (2). Both the chemical and mechanical properties of the ECM have been shown to influence normal and malignant cell behavior. For instance, mesenchymal stem cells differentiate into specific lineages that are dependent on matrix stiffness (3) , while tumor cells undergo changes in cell behavior and gene expression in response to matrix stiffness (4). ECM remodeling is implicated in tumor progression and includes changes in both the chemical and mechanical properties of the ECM (5) that can be a result of 1.) increased deposition of stromal ECM, 2.) enhanced contraction of ECM fibrils, and 3.) altered collagen alignment and ECM stiffness. In addition, remodeling of the ECM may alter whether tumor cells employ proteolytic degradation mechanisms during invasion and metastasis. Tumor cells respond to such changes in ECM remodeling through altered intracellular signaling and cell cycle control that lead to enhanced proliferation, loss of normal tissue architecture, and local tumor cell migration and invasion into the surrounding stromal tissue (6). This review will focus on the bi-directional interplay between the mechanical properties of the ECM and changes in integrin-mediated signal transduction events in an effort to elucidate cell behaviors during tumor progression.
Integrins in mammary-stem-cell biology and breast-cancer progression - a role in cancer stem cells?
Journal of Cell Science, 2008
Cancer cells with stem cell-like properties (cancer stem cells) are believed to drive cancer and are associated with poor prognosis. Data from mouse models have demonstrated that integrins, the major cellular receptors for extracellular-matrix components, have essential roles both during cancer initiation and progression, and during cell differentiation in normal development. By presenting an overview of the role of integrins in stem-cell biology and in cancer progression, this Commentary aims to present evidence for a role of integrins in the biology of cancer stem cells. Given the recent interest in the role of integrins in breast-cancer initiation and progression, we focus on the role of the members of the integrin family and their coupled signaling pathways in mammary-gland development and tumorigenesis.
Integrin activation controls metastasis in human breast cancer
Proceedings of The National Academy of Sciences, 2001
Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3
Biochemical and biophysical research communications, 2018
Integrins are the major cell adhesion glycoproteins involved in cell-extracellular matrix (ECM) interaction and metastasis. Further, glycosylation on integrin is necessary for its proper folding and functionality. Herein, differential expression of integrins viz., αvβ3 and αvβ6 was examined in MDA-MB-231, MDA-MB-468 and MCF-10A cells, which signify three different stages of breast cancer development from highly metastatic to non-tumorigenic stage. The expression of αvβ3 and αvβ6 integrins at mRNA and protein levels was observed in all three cell lines and the results displayed a distinct pattern of expression. Highly metastatic cells showed enhanced expression of αvβ3 than moderate metastatic and non-tumorigenic cells. The scenario was reversed in case of αvβ6 integrin, which was strongly expressed in moderate metastatic and non-tumorigenic cells. N-glycosylation of αvβ3 and αvβ6 integrins is required for the attachment of cells to ECM proteins like fibronectin. The cell adhesion pr...
Cancer Research, 1996
The involvement of the a6@3lintegrin, a laminin receptor, in breast carcInoma progression needs to be addressed rigorously. We report that a human breast carcinoma cell lIne, MDA-MB.435, known to be highly Invasive and metastatic, expresses three potential Integrin laminin recep tors: a2fil, a3@.31, and a6fil, but uses only a6@3lto mediate adhesion and migration on laminin matrices. To Investigate the contribution of a6@J1 to the aggressive behavior of these cells, we developed a dominant-negative strategy for knocking out a6fil function that involved expression of a cytoplasmic domain deletion mutant of the @34 integrin subunit by cDNA transfection. Stable transfectants of MDA-MB-435 cells that expressed this mutant fi4 subunit were inhibited dramatically in their ability to adhere and migrate on laminin matrices, and their capacity to Invade Matrigel was reduced significantly. These findings support the hypothesis that a6@31is important for breast cancer progression. Moreover, this approach is a powerful method that should be useful in assessing the role of a6fil in other cells.
Journal of Biological Chemistry, 2012
Background: Integrin-mediated ECM adhesion is required for mammary epithelial proliferation, but the mechanism is not known. Results: Gene deletion studies show that 1-integrin-null mammary epithelial cells retain 3-integrins and the ability to undergo two-dimensional migration, and Rac1 rescues their proliferation defect. Conclusion: 1-Integrins uniquely control proliferation in mammary cells via Rac1, whereas 3-integrins support two-dimensional migration. Significance: Specific -integrin-containing adhesions determine different cell-fate responses.
Journal of Cellular Physiology, 2010
Estrogen effects on mammary gland development and differentiation are mediated by two receptors (ERa and ERb). Estrogen-bound ERa induces proliferation of mammary epithelial and cancer cells, while ERb is important for maintenance of the differentiated epithelium and inhibits proliferation in different cell systems. In addition, the normal breast contains higher ERb levels compared to the early stage breast cancers, suggesting that loss of ERb could be important in cancer development. Analysis of ERbÀ/À mice has consistently revealed reduced expression of cell adhesion proteins. As such, ERb is a candidate modulator of epithelial homeostasis and metastasis. Consequently, the aim of this study was to analyze estrogenic effects on adhesion of breast cancer cells expressing ERa and ERb. As ERb is widely found in breast cancer but not in cell lines, we used ERa positive T47-D and MCF-7 human breast cancer cells to generate cells with inducible ERb expression. Furthermore, the colon cancer cell lines SW480 and HT-29 were also used. Integrin a1 mRNA and protein levels increased following ERb expression. Integrin b1-the unique partner for integrin a1-increased only at the protein level. ERb expression enhanced the formation of vinculin containing focal complexes and actin filaments, indicating a more adhesive potential. This was confirmed by adhesion assays where ERb increased adhesion to different extracellular matrix proteins, mostly laminin. In addition, ERb expression was associated to less cell migration. These results indicate that ERb affects integrin expression and clustering and consequently modulates adhesion and migration of breast cancer cells.