Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients

Pérez-Tenorio, Gizeh; Stål, Olle

doi:10.1038/sj.bjc.6600126

Cited by 365 publications

(317 citation statements)

References 38 publications

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“…The typical pattern of pAKT staining we observed included both cytoplasmic and nuclear immunostaining. This is consistent with most other reports for malignant cells in which the reported subcellular localisation of pAKT staining is cytoplasmic (Gupta et al, 2002;Perez-Tenorio and Stal, 2002) and nuclear (Dhawan et al, 2002;Itoh et al, 2002). Membrane staining is commonly observed in nontransformed cells and has also been reported in malignant cells though usually as a component of cytoplasmic staining (Yuan et al, 2000).…”

Section: Incidence Of Activated Akt In Pancreatic Adenocarcinoma Tumourssupporting

confidence: 91%

“…In vitro data have coupled AKT to the survival pathway of the transcription factor NF-kB. This is particularly interesting given three observations: (1) the frequent constitutive activation of NF-kB in various cancers including pancreatic tumour specimens (Wang et al, 1999), (2) the nuclear immunostaining pattern of pAKT frequently observed in various tumours (Dhawan et al, 2002;Itoh et al, 2002;Perez-Tenorio and Stal, 2002), and (3) the correlation of pAKT immunostaining and nuclear localisation of the p65 subunit of NF-kB in melanoma specimens (Dhawan et al, 2002). We have previously shown in the MIA-PaCa-2 cells that AKT is coupled to NF-kB activation and alters levels of various members of the apoptosis-regulating BCL-2 family (Fahy et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Constitutive activation of AKT provides a potent antiapoptotic signal in cancer cells conferring chemo-and radioresistance (Brognard et al, 2001;West et al, 2002). To date, there have been a few studies on the incidence of AKT activation in various tumours using archived pathologic specimens (Dhawan et al, 2002;Gupta et al, 2002;Itoh et al, 2002;Malik et al, 2002;Perez-Tenorio and Stal, 2002). While these reports correlate AKT activation with some biologic property of the tumour, none has examined potential upstream activating mechanisms.…”

mentioning

confidence: 99%

“…While these reports correlate AKT activation with some biologic property of the tumour, none has examined potential upstream activating mechanisms. In prostate cancer, the AKT activation occurred in 33 out of 125 specimens and was more frequent in higher Gleason grade cancers (Malik et al, 2002); in colon cancer, the AKT activation was observed in 30 out of 65 tumours and associated with advanced clinicopathologic stage (Itoh et al, 2002); in breast cancer, the AKT activation was frequently observed (50 out of 93) and predicted a worse prognosis in endocrine treated patients (Perez-Tenorio and Stal, 2002); in melanoma, the AKT activation was observed in eight out of 12 specimens and the incidence of AKT activation was more common than in precursor lesions (Dhawan et al, 2002); and in head and neck squamous cell carcinoma, the AKT activation was observed in 25 out of 38 (66%) specimens and correlated with local recurrence (Gupta et al, 2002).…”

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confidence: 99%

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Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

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When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P ¼ 0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P ¼ 0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

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Section: Incidence Of Activated Akt In Pancreatic Adenocarcinoma Tumourssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

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“…Indeed, phosphorylated Akt level is increased in 30-40% of breast cancers, where it promotes epithelial-to-mesenchymal transition and tumor progression to an invasive and metastatic carcinoma (Liu et al, 2007). Consequently, Akt activation is associated to a decrease in disease-free survival and may have prognostic relevance in breast cancer (Perez-Tenorio and Stal 2002). Several factors are known to activate the PI3K/Akt pathway including estrogens, IGF, EGF and HER2/neu.…”

Section: Discussionmentioning

confidence: 99%

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

et al. 2011

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Somatostatin receptors (sst1-5) are present in different types of tumors, where they inhibit key cellular processes such as proliferation and invasion. Although ssts are densely expressed in breast cancer, especially sst2, their role and therapeutic potential remain uncertain. Recently, we identified a new truncated sst5 variant, sst5TMD4, which is related to the abnormal response of certain pituitary tumors to treatment with somatostatin analogs. Here, we investigated the possible role of sst5TMD4 in breast cancer. This study revealed that sst5TMD4 is absent in normal mammary gland, but is abundant in a subset of poorly differentiated human breast tumors, where its expression correlated to that of sst2. Moreover, in the MCF-7 breast cancer model cell, sst5TMD4 expression increased malignancy features such as invasion and proliferation abilities (both in cell cultures and nude mice). This was likely mediated by sst5TMD4-induced increase in phosphorylated extracellular signal-regulated kinases 1 and 2 and p-Akt levels, and cyclin D3 and Arp2/3 complex expression, which also led to mesenchymal-like phenotype. Interestingly, sst5TMD4 interacts physically with sst2 and thereby alters its signaling, enabling disruption of sst2 inhibitory feedback and providing a plausible basis for our findings. These results suggest that sst5TMD4 could be involved in the pathophysiology of certain types of breast tumors.

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