Β1-INTEGRINS Signaling and Mammary Tumor Progression in Transgenic Mouse Models: Implications for Human Breast Cancer (original) (raw)
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Cancer Cell, 2004
Despite evidence demonstrating the role of 1-integrin in the regulation of cancer cell proliferation in vitro, the importance of this cell adhesion receptor during the initiation and progression of epithelial tumors in vivo remains unclear. Here we have used the Cre/LoxP1 recombination system to disrupt 1-integrin function in the mammary epithelium of a transgenic mouse model of human breast cancer. Using this approach, we show that 1-integrin expression is critical for the initiation of mammary tumorigenesis in vivo, and for maintaining the proliferative capacity of late-stage tumor cells. These observations provide a direct demonstration that 1-integrin plays a critical role in both the initiation and maintenance of mammary tumor growth in vivo.
Integrin signaling in mammary epithelial cells and breast cancer
2012
Cells sense and respond to the extracellular matrix (ECM) by way of integrin receptors, which facilitate cell adhesion and intracellular signaling. Advances in understanding the mammary epithelial cell hierarchy are converging with new developments that reveal how integrins regulate the normal mammary gland. But in breast cancer, integrin signaling contributes to the development and progression of tumors. This paper highlights recent studies which examine the role of integrin signaling in mammary epithelial cells and their malignant counterparts.
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
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.
2005
AvB3 or AvB5 integrins are widely expressed on blood and endothelial cells. Inhibition of the functions of these integrins has been reported to suppress neovascularization and tumor growth, suggesting that they may be critical modulators of angiogenesis. However, mice lacking these integrins exhibit extensive angiogenesis. Tumors arising from s.c. injections of tumor cells into mice lacking one or both integrins show enhanced tumor growth compared with growth in control mice due to both increased angiogenesis and to altered innate immune response. Other data suggest additional roles for these integrins, on either platelets or the tumor cells themselves, in enhancing tumor progression and metastasis. Here, we investigate the involvement of B3 and B5 integrins in the development and progression of mammary carcinomas. We intercrossed mouse mammary tumor virus (MMTV)-c-neu transgenic mice with B3 or B5 or B3B5 integrin-deficient mice and observed that multiple, large mammary tumors deve...
Integrin-mediated signal transduction in transgenic mouse models of human breast cancer
Breast Cancer …, 2003
The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, however, remain problematic. Recent advances in genomic technologies offer significant opportunities to identify critical changes that occur during cancer evolution and to distinguish in a complex and comprehensive manner the key similarities and differences between mouse models and human cancer. Comparisons between mouse and human tumors are being performed using comparative genomic hybridization, gene expression profiling, and proteomic analyses. The appropriate use of genetically engineered mouse models of mammary cancer in preclinical studies remains an important challenge which may also be aided by genomic technologies. Genomic approaches to cancer are generating huge datasets that represent a complex system of underlying networks of genetic interactions. Mouse models offer a tremendous opportunity to identify such networks and how they relate to human cancer. The challenge of the future remains to decipher these networks in order to identify the genetic nodes of oncogenesis that may be important targets for chemoprevention and therapy.
The α2β1 integrin is a metastasis suppressor in mouse models and human cancer
Journal of Clinical Investigation, 2011
Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that β 1 integrins may stimulate metastasis of a number of cancers, expression of the β 1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the α 2 β 1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of α 2 β 1 integrin in normal breast epithelium and loss of α 2 β 1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding α 2 integrin, but not genes encoding α 1 , α 3 , or β 1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of α 2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the α 2 β 1 integrin functionally inhibits breast tumor metastasis, and α 2 expression may serve as an important biomarker of metastatic potential and patient survival. Conflict of interest: The authors have declared that no conflict of interest exists.
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.
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.
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...