The substrate domain of BCAR1 is essential for anti-estrogen-resistant proliferation of human breast cancer cells

Brinkman, Arend; Jong, Daniëlle de; Tuinman, Sietske; Azaouagh, Najat; Agthoven, Ton van; Dorssers, Lambert C. J.

doi:10.1007/s10549-009-0403-4

Cited by 19 publications

(18 citation statements)

References 47 publications

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“…Although displaying highly conserved structural features with p130CAS, NEDD9 does not correlate with oestrogen resistance in breast cancer 126 . However, NEDD9 is overexpressed in imatinib-resistant gastrointestinal stromal tumour cells 128 , suggesting that over-expression of a specific CAS family adaptor is selective for the acquirement of resistance to therapy in different cancer subtypes.…”

Section: Clinical Implications Of Integrin Adaptorsmentioning

confidence: 94%

“…Although it has been reported that a possible mechanism through which p130CAS induces tamoxifen resistance is its binding to BCAR3/AND34, a putative GEF for RALA, RAP, and RRAS GTPases 124 , the exact mechanism by which p130CAS and BCAR3 induce anti-oestrogen resistance remains unclear. In addition, it has been suggested that both serine and tyrosine phosphorylation of p130CAS are required for mediating oestrogen resistance 125,126 .…”

Section: Clinical Implications Of Integrin Adaptorsmentioning

confidence: 99%

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Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects regulated by these adaptors in tumours might be crucial for the identification of novel targets and the development of innovative therapeutic strategies for human cancer. In this review we will discuss the relevance of adaptor proteins in signalling originating from integrin-mediated cell-extracellular matrix (ECM) adhesion and growth factor stimulation within the context of cell transformation and tumour progression.Herein, we will specifically underline the contribution of p130CAS, NEDD9, CRK, and the IPP complex (ILK, PINCH and PARVIN) to cancer, along with the more recently identified p140CAP.

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Section: Clinical Implications Of Integrin Adaptorsmentioning

confidence: 94%

Section: Clinical Implications Of Integrin Adaptorsmentioning

confidence: 99%

Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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“…53,54 Screening for BCAR1 phosphorylation levels could be even more powerful. 55,56 On the other hand, only a few mutations have been identified so far in each of the 3 NSP genes as well as in BCAR1 and NEDD9 in different types of cancers (sanger.ac.uk/cosmic), and no information is yet available on the functional effects of the mutations or their relevance to cancer development and malignancy. With regard to therapy, siRNA-based strategies will allow the reduction of NSP-CAS complexes and their malignant activities.…”

Section: Monographsmentioning

confidence: 99%

NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer

et al. 2012

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The CAS (CRK-associated substrate) family of adaptor proteins comprises 4 members, which share a conserved modular domain structure that enables multiple protein-protein interactions, leading to the assembly of intracellular signaling platforms. Besides their physiological role in signal transduction downstream of a variety of cell surface receptors, CAS proteins are also critical for oncogenic transformation and cancer cell malignancy through associations with a variety of regulatory proteins and downstream effectors. Among the regulatory partners, the 3 recently identified adaptor proteins constituting the NSP (novel SH2-containing protein) family avidly bind to the conserved carboxy-terminal focal adhesion-targeting (FAT) domain of CAS proteins. NSP proteins use an anomalous nucleotide exchange factor domain that lacks catalytic activity to form NSP-CAS signaling modules. Additionally, the NSP SH2 domain can link NSP-CAS signaling assemblies to tyrosine-phosphorylated cell surface receptors. NSP proteins can potentiate CAS function by affecting key CAS attributes such as expression levels, phosphorylation state, and subcellular localization, leading to effects on cell adhesion, migration, and invasion as well as cell growth. The consequences of these activities are well exemplified by the role that members of both families play in promoting breast cancer cell invasiveness and resistance to antiestrogens. In this review, we discuss the intriguing interplay between the NSP and CAS families, with a particular focus on cancer signaling networks.

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“…20 Subsequently, intensive studies concentrated on the carcinogenic mechanisms of BCAR1 in breast cancer. 21–24 Breast cancer with elevated BCAR1 levels is prone to relapse and has poor prognosis. 25 As a scaffolding and adapter protein, BCAR1 has attracted growing attention due to its tumorigenic roles, e.g., invasion and migration, and has been implicated in the carcinogenesis and prognosis in a variety of malignancies, i.e., ovarian, liver, esophagus, and oral cavity.…”

Section: Discussionmentioning

confidence: 99%

Increased BCAR1 Predicts Poor Outcomes of Non-small Cell Lung Cancer in Multiple-Center Patients

et al. 2013

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Objective We aimed to study the prognostic value of BCAR1 expression and its associations with clinical-demographical characteristics in multiple centers of non-small cell lung cancer (NSCLC) patients. Methods Gene expression microarray (mRNA) of 77 adenocarcinomas from Mayo Clinic, RNA-sequencing of 508 NSCLC from The Cancer Genome Atlas (TCGA), and immunohistochemistry(IHC) stain of BCAR1-protein expression in 150 cases from Daping Hospital were included in the study. The association of mRNA or protein expression with patient clinical characteristics and overall survival was assessed in each dataset. We also predicted microRNAs (miRNA) that target BCAR1- using bioinformatics prediction tools and evaluated miRNA expression patterns with BCAR1 expression in miRNA-sequencing data of 74 lung cancer cases from TCGA dataset. Results In the Mayo Clinic dataset, a higher BCAR1-mRNA level was significantly correlated with more advanced tumor-stage and lymphatic metastasis. Similar changes were observed in the TCGA RNA-seq dataset. Additionally, higher BCAR1-mRNA levels predicted poorer survival in adenocarcinoma and squamous carcinoma from the TCGA dataset. The protein levels in the adenocarcinoma cases with lymphatic metastasis were significantly higher than of those without metastasis. Tumor tissues demonstrated remarkably higher levels of protein compared with matched normal tissues although there was no significant difference in BCAR1-mRNA expression between tumor and matched normal tissues was detected. In miRNAs that were down-regulated in the tumors, Let-7f-2 and miR-22 differed the most (P<0.001 and P=0.007, respectively). Conclusion We confirmed that increased BCAR1 expression predicts poorer prognosis in NSCLC. We postulate mRNA-protein decoupling of BCAR1 may be a result of reduced inhibition of specific miRNAs in tumor tissues, which warrants further study.

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The substrate domain of BCAR1 is essential for anti-estrogen-resistant proliferation of human breast cancer cells

Cited by 19 publications

References 47 publications

Integrin signalling adaptors: not only figurants in the cancer story

Integrin signalling adaptors: not only figurants in the cancer story

NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer

Increased BCAR1 Predicts Poor Outcomes of Non-small Cell Lung Cancer in Multiple-Center Patients

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