The alpha2 beta1 integrin is a metastasis suppressor in mouse models and human cancer (original) (raw)
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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.
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
Molecular Cancer Research, 2014
Significant evidence implicates a3b1 integrin in promoting breast cancer tumorigenesis and metastasis-associated cell behaviors in vitro and in vivo. However, the extent to which a3b1 is actually required for breast cancer metastasis remains to be determined. We used RNA interference to silence a3 integrin expression by approximately 70% in 4T1 murine mammary carcinoma cells, a model of aggressive, metastatic breast cancer. Loss of a3 integrin reduced adhesion, spreading, and proliferation on laminin isoforms, and modestly reduced the growth of orthotopically implanted cells. However, spontaneous metastasis to lung was strikingly curtailed. Experimental lung colonization after tail vein injection revealed a similar loss of metastatic capacity for the a3-silenced (a3si) cells, suggesting that critical, a3-dependent events at the metastatic site could account for much of a3b1 0 s contribution to metastasis in this model. Reexpressing a3 in the a3si cells reversed the loss of metastatic capacity, and silencing another target, the small GTPase RhoC, had no effect, supporting the specificity of the effect of silencing a3. Parental, a3si, and a3-rescued cells, all secreted abundant laminin a5 (LAMA5), an a3b1 integrin ligand, suggesting that loss of a3 integrin might disrupt an autocrine loop that could function to sustain metastatic growth. Analysis of human breast cancer cases revealed reduced survival in cases where a3 integrin and LAMA5 are both overexpressed. Implications: a3 integrin or downstream effectors may be potential therapeutic targets in disseminated breast cancers, especially when laminin a5 or other a3 integrin ligands are also over-expressed. Mol Cancer Res; 12(1); 143-54. Ó2013 AACR.
Biphasic α2β1 Integrin Expression in Breast Cancer Metastasis to Bone
International Journal of Molecular Sciences
Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2β1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2β1 in the context of bone metastasis. In this study, we aimed to understand the role of α2β1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tum...
Diagnostic Pathology, 2012
Background: The main focus of several studies concerned with cancer progression and metastasis is to analyze the mechanisms that allow cancer cells to interact and quickly adapt with their environment. Integrins, a family of transmembrane glycoproteins, play a major role in invasive and metastatic processes. Integrins are involved in cell adhesion in both cell-extracellular matrix and cell-cell interactions, and particularly, β1 integrin is involved in proliferation and differentiation of cells in the development of epithelial tissues. This work aimed to investigate the putative role of β1 integrin expression on survival and metastasis in patients with breast invasive ductal carcinoma (IDC). In addition, we compared the expression of β1 integrin in patients with ductal carcinoma in situ (DCIS). Methods: Through tissue microarray (TMA) slides containing 225 samples of IDC and 67 samples of DCIS, β1 integrin expression was related with several immunohistochemical markers and clinicopathologic features of prognostic significance. Results: β1 integrin was overexpressed in 32.8% of IDC. In IDC, β1 integrin was related with HER-2 (p = 0.019) and VEGF (p = 0.011) expression and it had a significant relationship with metastasis and death (p = 0.001 and p = 0.05, respectively). Kaplan-Meier survival analysis showed that the overexpression of this protein is very significant (p = 0.002) in specific survival (number of months between diagnosis and death caused by the disease). There were no correlation between IDC and DCIS (p = 0.559) regarding β1 integrin expression. Conclusions: Considering that the expression of β1 integrin in breast cancer remains controversial, specially its relation with survival of patients, our findings provide further evidence that β1 integrin can be a marker of poor prognosis in breast cancer.
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.
The integrin alpha 6 beta 1 promotes the survival of metastatic human breast carcinoma cells in mice
PubMed, 1997
The role of the integrin alpha 6 beta 1 in breast carcinoma progression was studied by targeted elimination of this integrin in MDA-MB-435 cells, a human breast carcinoma cell line that is highly metastatic in athymic mice. The strategy used is based on the finding that expression of a cytoplasmic domain deletion mutant of the beta 4-integrin subunit (beta 4-delta CYT) in MDA-MB-435 cells eliminates formation of the alpha 6 beta 1 heterodimer. MDA-MB-435 cells that lacked alpha 6 beta 1 expression (beta 4-delta CYT transfectants) formed tumors in athymic mice that were suppressed in their growth and that exhibited a significant increase in apoptosis in comparison to the control tumors. Unlike the control MDA-MB-435 cells, the beta 4-delta CYT transfectants were unable to establish metastatic foci in the lungs. Also, the control transfectants grew substantially better than the beta 4-delta CYT transfectants in the liver after intrahepatic injection because of extensive apoptosis in the beta 4-delta CYT transfectants. These data suggest that a major function of the alpha 6 beta 1 integrin in breast carcinoma is to facilitate tumorigenesis and promote tumor cell survival in distant organs.
Clinical Cancer Research, 2008
Purpose: The β4 integrin has been implicated in functions associated with the genesis and progression of carcinomas based on data obtained from cell lines and mouse models. Data on its expression and relevance to human carcinomas, however, are relatively scant. The aim of this study was to assess its expression and prognostic significance in human breast carcinomas.Experimental Design: We integrated data on β4 expression from multiple gene profiling studies of breast tumors of known clinical outcome with immunohistochemical analysis of 105 breast carcinomas, and we identified genes whose expression correlates with that of β4.Results: The expression of both β4 mRNA and protein is not homogeneous in breast cancer and it associates most significantly with the “basal-like” subtype of breast tumors (P = 0.008). No association between β4 and HER2 expression was evident from either gene profiling or immunohistochemical analysis. To gain insight into the relevance of β4 expression to human ...
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.