Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study

Santos, Paulo Sérgio Faro; Zanetti, Juliana da Silva; Ribeiro‐Silva, Alfredo; Beltrão, Eduardo Isidoro Carneiro

doi:10.1186/1746-1596-7-104

Cited by 80 publications

(59 citation statements)

References 53 publications

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“…␤1-Integrin is highly expressed in most tumors and is associated with a negative prognostic significance such as overall and disease-free survival, recurrence, and metastasis for head and neck and squamous cell carcinoma, melanoma, lung, breast, prostate, laryngeal, and pancreatic cancers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). A recent immunostaining study of 225 breast invasive ductal carcinomas (IDCs) showed that ␤1-integrin was overexpressed in 32.8% of patients with IDCs (13). Numerous studies show that focal adhesion kinase (FAK) which is downstream from ␤1-integrin is also a negative prognostic factor for breast cancer patients (18)(19)(20).…”

mentioning

confidence: 99%

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Hedrick

Lee

Doddapaneni

et al. 2016

Molecular and Cellular Biology

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cOverexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor ␤ (TGF-␤) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-␤ independent and dependent on regulation of ␤1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3=-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3=-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO 2 Me)] analog. The NR4A1 antagonists also inhibited TGF-␤-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-␤-induced cell migration. We also observed that NR4A1 regulates expression of both ␤1-and ␤3-integrins, and unlike other ␤1-integrin inhibitors which induce prometastatic ␤3-integrin, NR4A1 antagonists inhibit expression of both ␤1-and ␤3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. Cell adhesion and attachment are essential for tissue integrity and cellular homeostasis, and the heterodimeric integrin cell surface receptors play a critical role in these processes (1-3). There are 18 different ␣ subunits and 8 different ␤ subunits that form 24 ␣␤-integrin receptor heterodimers, and the large 12-member ␤1-integrin subgroup bind multiple extracellular matrix (ECM) molecules to activate multiple intracellular pathways and also induce cross talk with other signaling systems (1-3). The functions of integrin heterodimers are highly tissue specific, and many human pathologies also involve integrin signaling (reviewed in references 4 and 5). ␤1-Integrin is highly expressed in most tumors and is associated with a negative prognostic significance such as overall and disease-free survival, recurrence, and metastasis for head and neck and squamous cell carcinoma, melanoma, lung, breast, prostate, laryngeal, and pancreatic cancers (6-17). A recent immunostaining study of 225 breast invasive ductal carcinomas (IDCs) showed that ␤1-integrin was overexpressed in 32.8% of patients with IDCs (13). Numerous studies show that focal adhesion kinase (FAK) which is downstream from ␤1-integrin is also a negative prognostic factor for breast cancer patients (18)(19)(20). The important functional role of ␤1-integrin has been demonstrated in mouse models expressing erbB2 under the control of the mouse mammary tumor virus and crossed with mammary tissue-specific ␤1-integrin-deficient mice. These mice exhibit a decrease in tumor volume, increased apoptosis, and decreased lung metastasis compared to animals expressing wild-type ␤1-integrin (21-23). Although small molecules, peptides, and antibodies that inhibit ␤1-integrin signaling have been developed, clinical agents that target ␤1-integrin for cancer chemotherapy are not cur...

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mentioning

confidence: 99%

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Hedrick

Lee

Doddapaneni

et al. 2016

Molecular and Cellular Biology

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“…Supporting this model are the results of genomic sequencing approaches which reveal that mutations in a wide range of ECM components, integrins and cytoskeletal components occur in primary breast cancers (Ellis et al, 2012;Shah et al, 2012). Furthermore, activating mutations in b1 integrin increase the susceptibility for tumour formation derived from epithelial cells in the skin, whereas perturbed b1 integrin expression correlates with poor prognosis in breast cancer patients (dos Santos et al, 2012;Ferreira et al, 2009). …”

Section: Integrins and Polarity In Cancermentioning

confidence: 74%

Integrins and epithelial cell polarity

Lee

Streuli

2014

Journal of Cell Science

125

117

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Cell polarity is characterised by differences in structure, composition and function between at least two poles of a cell. In epithelial cells, these spatial differences allow for the formation of defined apical and basal membranes. It has been increasingly recognised that cell-matrix interactions and integrins play an essential role in creating epithelial cell polarity, although key gaps in our knowledge remain. This Commentary will discuss the mounting evidence for the role of integrins in polarising epithelial cells. We build a model in which both inside-out signals to polarise basement membrane assembly at the basal surface, and outside-in signals to control microtubule apical-basal orientation and vesicular trafficking are required for establishing and maintaining the orientation of epithelial cell polarity. Finally, we discuss the relevance of the basal integrin polarity axis to cancer.

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“…In certain types of cancer, β1 integrin is associated with poor prognosis or metastasis, including in prostatic cancer (15,24), melanoma (25), gastric carcinoma (26) and hypopharyngeal squamous cell carcinoma (27). However, in other types of cancer, including breast cancer, studies have reported different or contradictory conclusions (28)(29)(30). This suggests that additional clinical observations and studies are required to understand this association.…”

Section: Metastasismentioning

confidence: 81%

β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication (Review)

et al. 2018

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Abstract.Integrins are transmembrane glycoproteins that consist of an α and a β subunit. Specific integrin heterodimers preferentially bind to distinct extracellular matrix (ECM) proteins to affect the characteristics of cells or the components of the ECM. Among the different integrins, β1 and β3 integrins serve essential roles in the progression of different cancer-associated processes, including the initiation, proliferation, survival, migration and invasion. Furthermore, previous studies have revealed a ratio between these two integrins in cancer cells, which also demonstrated that the functions of these two integrins are paradoxical. This indicated that the proliferation and metastasis of cancer cells are not always parallel and may be considered independently maintained. Additionally, the present review may assist in understanding certain aspects of cancer, and in making clinical decisions in a novel and more comprehensive manner. IntroductionIntegrins are transmembrane glycoproteins that consist of an α subunit and a β subunit. A total of eight different β subunits may dimerize, in limited combinations, with 18α subunits to form ≥24 distinct integrins (1,2). Specific integrin heterodimers preferentially bind to distinct extracellular matrix (ECM) proteins. Integrins may bind the ligands in ECM directly, including fibronectin and laminin, to affect the characteristics of cells or the components of ECM. Regarding cancer cells, integrins serve roles in numerous aspects, including proliferation, survival, migration and invasion (1).Integrins primarily affect cells in two ways, the first is through binding with proteins directly, including talin, vinculin and filamin, which may regulate the actin cytoskeleton of cells (3). The other is by phosphorylating the relative kinases, including focal adhesion kinases (FAKs), proto-oncogene tyrosine-protein kinase (Src)-family kinases (SFKs) and integrin-linked kinase (ILK), to activate or cooperate with the other cell signaling pathways (1,4). Additionally, integrin clustering on the cell surface and trafficking from the endosomes may affect the ligand affinity and quantity of the protein on cell surface (5-7).Among the different integrins, β1 and β3 integrins serve essential roles in the progression of different types of cancer (1,2). Furthermore, previous studies investigating the association between these two integrins have demonstrated many different perspectives (8-11), together providing a novel and more comprehensive understanding of cancer. Functions of β1 integrin in cancerIn tumors, the β1 subunit of integrin may combine with different α subunits, including α4, α5 and α2, to affect the characteristics of cancer cells, and the progression of tumors (1). The primary function of β1 integrin is to form focal adhesion between cancer cells and ECM. This adhesion is the basis for the survival of cancer cells and is also associated with their migratory and metastatic capabilities (2). There are series of proteins in the cytoplasm, including talin, kindlin and ILK, ...

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Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study

Cited by 80 publications

References 53 publications

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Integrins and epithelial cell polarity

β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication (Review)

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