Enhanced insulin signaling via Shc in human breast cancer

Finlayson, Christina; Chappell, James; Leitner, J. Wayne; Goalstone, Marc L.; Garrity, Maureen; Nawaz, Samia; Ciaraldi, Theodore P.; Draznin, Boris

doi:10.1016/s0026-0495(03)00311-1

Cited by 28 publications

(23 citation statements)

References 41 publications

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“…in animals and humans), leads to overstimulation of farnesyltransferase, and excessive farnesylation and membrane association of Ras proteins, thereby increasing cellular responsiveness to other growth factors. This potentiation of the mitogenic effects of other growth factors becomes critical in the pathophysiology of progression of cancer and vascular disease [15][16][17].…”

Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

“…Overall, the ability of insulin to potentiate action of IGF-1, EGF, PDGF and VEGF has been observed in a variety of tissues, including vascular smooth muscle cells, endothelial cells, adipocytes, fibroblasts, liver cells and breast cancer cells [9,10,13,[15][16][17][18][19][20][21]. This effect of insulin has been consistently observed whenever metabolic insulin resistance along the PI3K pathway is present.…”

Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

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Mitogenic action of insulin: friend, foe or ‘frenemy’?

Draznin

2009

Diabetologia

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Either endogenous or exogenous hyperinsulinaemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras proteins. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. The stimulatory effect of hyperinsulinaemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin.

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Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

Mitogenic action of insulin: friend, foe or ‘frenemy’?

Draznin

2009

Diabetologia

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“…Furthermore, high expression of FAK in breast cancer is related to activation of AKT (Schmitz et al, 2005) and to the overexpression of receptor molecules such as ErbB2/ Her2 and EGFR (Lemmon, 2003). Lastly, the roles of amplified Shc signalling, substrates for most receptor tyrosine kinases, in breast tumourgenesis and metastasis were studied recently (Mauro et al, 1999;Dankort et al, 2001;Finlayson et al, 2003).…”

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confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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“…Accordingly, inhibition of Rho signaling results in the abrogation of the metastatic phenotype elicited by CD44 (Bourguignon, Zhu et al 1999). RhoA has also been found to be involved in insulin signaling via Shc in human breast cancer (Finlayson, Chappell et al 2003). Overexpression of insulin receptors correlates with development, progression and outcome of breast cancer, and insulin signaling involves hyperphosphorylation of Shc.…”

Section: Rho Gtpases In Breast Tumorsmentioning

confidence: 99%

“…Overexpression of insulin receptors correlates with development, progression and outcome of breast cancer, and insulin signaling involves hyperphosphorylation of Shc. Hence, Shc leads to the activation of geranyl transferases, which results in an increased amount of prenylated RhoA in the tumor tissue compared with normal mammary tissue (Finlayson, Chappell et al 2003). Furthermore, RhoA has been reported to increase the metastatic potential of tumor cells via its ability to promote tumor angiogenesis through the downregulation of thrombospodin-1 (Tsp-1) (Watnick, Cheng et al 2003).…”

Section: Rho Gtpases In Breast Tumorsmentioning

confidence: 99%