Role of Src expression and activation in human cancer

Irby, Rosalyn; Yeatman, Timothy J.

doi:10.1038/sj.onc.1203912

Cited by 779 publications

(648 citation statements)

References 68 publications

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“…Unlike v-src, the human cellular homologue c-src was found to be only tumorigenic and felt by some not to play a large role in the pathogenesis of human malignancies [13]. Recently, however, aberrant activation and expression of c-src has been associated with human disease, including malignancies of the lung, skin, colon, ovary, endometrium, head and neck area and breast [12]. This has lead to the current hypothesis that c-src may facilitate the action of other signaling proteins, rather than being a dominant transforming agent.…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant expression and activation of src-family kinases have been implicated in a number of human malignancies but thus far they have not proven to be effective clinical targets [12][13]. Despite this, molecular studies continue to show src to play a potential role in clinically important pathways in breast cancer including the steroid and peptide hormone signaling pathways [14][15].…”

Section: Introductionmentioning

confidence: 99%

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Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

Finn

Dering

Ginther

et al. 2007

Breast Cancer Res Treat

370

288

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Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-tomesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 lM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40-59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (v 2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with ''triplenegative'' breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

Finn

Dering

Ginther

et al. 2007

Breast Cancer Res Treat

370

288

View full text Add to dashboard Cite

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“…C-Src is largely involved in pathophysiology of osteoblasts (Marzia et al, 2000) and CD99 isoforms differently affect tumour metastasis K Scotlandi et al prostate cancer (Jee et al, 2003;Recchia et al, 2003) along with the significant role that it plays in the regulation of crucial processes implicated in the pathogenesis and progression of tumours, such as cell cycle, migration, resistance to anoikis and anchorage independence (Irby and Yeatman, 2000). Therefore, we evaluated its role as a possible mediator of CD99 functions.…”

Section: Differences In Migration and Metastasis Are Related To Cd99mentioning

confidence: 99%

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

et al. 2007

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CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules.

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“…In normal cells, the kinase activity of c-Src is rigorously controlled by the negative regulator, C-terminal Src kinase (Csk) (Okada et al, 1991); thus, even when c-Src is abundantly expressed, its oncogenic potential is suppressed. The c-src gene is rarely mutated, but c-Src function is nonetheless upregulated in some cancer cells (Irby et al, 1999;Irby and Yeatman, 2000). Therefore, it has been hypothesized that disruption of the strict regulation of c-Src signaling triggers cancer progression, although the underlying mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

et al. 2011

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The tyrosine kinase c-Src is upregulated in various human cancers; however, the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. Here we show that downregulation of microRNA (miR)-542-3p is tightly associated with tumor progression via c-Src-related oncogenic pathways. In c-Src-transformed fibroblasts and human cancer cells that overexpress c-Src, miR-542-3p is substantially downregulated, and the ectopic expression of miR-542-3p suppresses tumor growth. We identified the integrin-linked kinase (ILK) as a conserved target of miR-542-3p. ILK upregulation promotes cell adhesion and invasion by activating the integrin-focal adhesion kinase (FAK)/c-Src pathway, and can also contribute to tumor growth via the AKT and glycogen synthase kinase 3b pathways. MiR-542-3p expression is downregulated by the activation of c-Src-related signaling molecules, including epidermal growth factor receptor, K-Ras and Ras/ Raf/mitogen-activated protein kinase/extracellular signalregulated kinase. In human colon cancer tissues, downregulation of miR-542-3p is significantly correlated with the upregulation of c-Src and ILK. Our results suggest that the novel c-Src-miR-542-3p-ILK-FAK circuit plays a crucial role in controlling tumor progression.

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Role of Src expression and activation in human cancer

Cited by 779 publications

References 68 publications

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

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