High expression of focal adhesion kinase (p125FAK) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome

Schmitz, Klaus; Grabellus, Florian; Callies, R.; Otterbach, Friedrich; Wohlschlaeger, Jeremias; Levkau, Bodo; Kimmig, Rainer; Schmid, Kurt Werner; Baba, Hideo A.

doi:10.1186/bcr977

Cited by 68 publications

(68 citation statements)

References 29 publications

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“…Consistent with previous findings in other cell types (Sanders and Basson, 2000;Schmitz et al, 2005;Vulin et al, 2005;Stulic et al, 2007), we found an enhanced activation of Src, ERK, PI3K, and Akt in A549 lung cancer cells. The role of FAK in the activation of these effectors was noted through their downregulated activation after the depletion of FAK.…”

Section: Discussionsupporting

confidence: 82%

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

et al. 2009

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BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in a variety of cancers, such as breast, colon, prostate, ovary, and lung cancers. However, the mechanism by which extracellular matrix fibronectin stimulates lung cancer cell migration and invasion through FAK remains to be investigated. METHODS: The signalling pathways in fibronectin-mediated lung cancer cell migration and invasion were examined using western blotting. The metastasis function was detected by wound healing, migration and invasion assays. Further, RNA interference and kinase inhibitors were also used to study the downstream signals. RESULTS: In this study, we examined the FAK signalling pathways in relation to calpain-2 and RhoA in fibronectin-mediated lung cancer cell migration and invasion. We found that A549 lung epithelial cells stimulated by fibronectin showed increased phosphorylation of FAK and its downstream targets, Src, ERK1/2, phosphatidylinositol 3 0 -kinase (PI3K), and Akt. Consistent with this observation, depletion of FAK by siRNA resulted in the inhibition of Src, ERK1/2, PI3K, and Akt activity. In addition, the Src inhibitor, PP2, blocked the phosphorylation of FAK, ERK1/2, PI3K, and Akt. Conversely, inhibition of MEK1/2 using PD98059 reduced the expression of matrix metalloproteinase-9 (MMP9) and calpain-2. The PI3K inhibitor, LY294002, further blocked the expression of MMP9 and RhoA. Inhibition of both MEK1/2 and PI3K caused reduced cell migration and invasion. CONCLUSIONS: Our data suggest that fibronectin-mediated activation of FAK that leads to lung cancer metastasis could occur through ERK or PI3K/Akt regulation of MMP9/calpain-2 or MMP9/RhoA activity, respectively.

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Section: Discussionsupporting

confidence: 82%

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

et al. 2009

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“…However, the levels of FAK (Y861) appeared to be increased in the HER2C cells. Although some reports have suggested that elevated FAK expression is associated with HER2 overexpression (Lark et al 2005, Schmitz et al 2005, our data on FAK Y861 are in accordance with recent studies that have demonstrated higher levels of FAK Y861 expression to be associated with poor prognostic indicators including the overexpression and activation of HER-2 (Vadlamudi et al 2002).…”

Section: Discussionsupporting

confidence: 82%

“…Moreover, FAK is key to the transduction of HER2 signalling in HER2-overexpressing MCF10A breast cells (Wang et al 2005) and in MUC4-overexpressing ovarian cancer cells, which have elevated HER2 activity (Ponnusamy et al 2008). FAK has been reported to be of prognostic significance in lung and oesophageal tumours (Itoh et al 2004), and in breast cancer, levels of FAK (PTK2) expression correlate strongly with poor tumour differentiation and are significantly associated with HER2 overexpression (Schmitz et al 2005). Interestingly, in tumours expressing HER2, the levels of FAK phosphorylation also appear to be significantly greater.…”

Section: Introductionmentioning

confidence: 99%

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Lazaro¹,

Smith

Goddard

et al. 2013

Endocrine-Related Cancer

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The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ERC)/HER2C breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ERC/HER2K (MCF7 and T47D) and ERC/HER2C (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878Gtrastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ERC/HER2C cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ERC/HER2C cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ERC/HER2C breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ERC/HER2C, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.

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“…On the other hand, hepatocyte growth factor receptor, c-Met (Edakuni et al, 2001;Parr and Jiang, 2001;Elliott et al, 2002;Lengyel et al, 2005), and the focal adhesion kinase (FAK) regulate multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis. 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).…”

mentioning

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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High expression of focal adhesion kinase (p125FAK) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome

Cited by 68 publications

References 29 publications

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

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

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