AKT Signaling Pathway in Invasive Ductal Carcinoma of the Breast: Correlation with ERα, ERβ and HER-2 Expression

Wang, Xiuling; Lee, Yi; Zhu, Yan; Zou, Jue; Hong, Yang; Zheng, Wei

doi:10.1177/030089161109700209

Cited by 15 publications

(10 citation statements)

References 21 publications

(19 reference statements)

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“…cervical cancer), [36, 37] but the increased stability of p53 mut is increasingly observed to be prognostic in breast cancer [72]. EGFR/HER2 +ve and ERα +ve breast cancers have previously been described to have elevated AKT activity [73, 74], we therefore aimed to correlate phospho-S48-NPM staining, with EGFR/HER2 positivity, p53 staining and tumor stage. Interestingly, the highest levels of p53 mut segregated with advanced tumor stage and the degree of phospho-S48-NPM staining correlated with EGFR/HER2 positivity and increased p53 staining intensity indicative of p53 mut (Fig.…”

Section: Resultsmentioning

confidence: 99%

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

et al. 2014

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Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53mut stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53mut status.

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Section: Resultsmentioning

confidence: 99%

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

et al. 2014

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“…It has been previously reported that endoplasmic reticulum stress-induced apoptosis is associated with a reduction in phospho-Akt (27,28). In addition, estrogen activates the PI3K-Akt pathway through ER α- and ER β-independent mechanisms in breast cancer (29,30). In the present study, the dephosphorylation of Akt at Ser473 was found to be involved in apoptosis induced by endoplasmic reticulum stress.…”

Section: Discussionmentioning

confidence: 99%

Estrogen protects SGC7901 cells from endoplasmic reticulum stress-induced apoptosis by the Akt pathway

Feng

Deng

et al. 2013

Oncology Letters

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Several previous studies have demonstrated that estrogen may protect cancer cells from endoplasmic reticulum stress-induced apoptosis. However, the molecular mechanisms involved are not fully understood. In the present study, human gastric adenocarcinoma SGC7901 cells were treated with tunicamycin (TM) to induce endoplasmic reticulum stress. This was demonstrated by increased glucose-regulated protein 78 expression and enhanced phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase. Endoplasmic reticulum stress induced caspase-3-mediated apoptosis with the inhibition of Akt; the latter of which was measured by the activity-dependent phosphorylation at Ser473 of Akt. Simultaneous treatment of 10−9 M 17β-estradiol (E2) with TM may protect SGC7901 cells from endoplasmic reticulum stress-induced apoptosis by counteracting the inhibitory effect of TM on Akt, causing an increase in the phosphorylation of Ser473-Akt. It was concluded that low concentrations of E2 may counteract endoplasmic reticulum stress-induced inactivation of Akt to block caspase-3-mediated apoptosis.

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“…The serine/threonine kinase Akt plays an essential role in various cellular processes, including cell growth and proliferation, metabolism and cell survival. Immunohistochemical analyses have shown that Akt is activated in many types of carcinoma and preneoplastic lesions, and Akt activation is associated with tumor progression and poor prognosis in various human malignancies [23][24][25][26][27] . However, in NSCLCs, the results so far are conflicting.…”

Section: Discussionmentioning

confidence: 99%

Expression of the Mammalian Target of Rapamycin Pathway Markers in Lung Adenocarcinoma and Squamous Cell Carcinoma

Kim

Lim

et al. 2012

Pathobiology

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Objective: We investigated whether the expression of mammalian target of rapamycin (mTOR) pathway components is associated with clinicopathologic characteristics and patient outcome in lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). Methods: We used immunohistochemistry to evaluate the expression of phosphorylated Akt (pAkt), mTOR, p70 ribosomal protein S6 kinase (p70S6K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in 91 cases of AC and 154 cases of SCC. Results: pAkt expression was positively correlated with the expression of mTOR (p < 0.001) and p70S6K (p < 0.001), and mTOR expression was positively correlated with p70S6K expression (p < 0.001). PTEN expression was inversely correlated with the expression of pAkt (p = 0.001), mTOR (p < 0.001) and p70S6K (p = 0.012). In addition, loss of PTEN expression, observed in 37.4% (34/91) of AC patients, was significantly associated with a higher histologic grade (p = 0.013), pathologic T stage (p = 0.016) and N stage (p < 0.001) and advanced TNM stage (p = 0.001), as well as a shorter overall survival of AC patients (p = 0.015). Conclusion: The high prevalence of PTEN loss and its association with aggressive tumor behavior and poor patient outcome in AC suggest that loss of PTEN expression is involved in AC progression and serves as a prognostic marker for patients with AC.

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AKT Signaling Pathway in Invasive Ductal Carcinoma of the Breast: Correlation with ERα, ERβ and HER-2 Expression

Abstract: The current study suggested that activity of the Akt signaling pathway may indicate a poor prognosis in patients with breast carcinoma. The results implied that estrogen can activate the PI3K-Akt pathway through ERa and ERβ-independent mechanisms in breast cancer.

Cited by 15 publications

References 21 publications

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

Estrogen protects SGC7901 cells from endoplasmic reticulum stress-induced apoptosis by the Akt pathway

Expression of the Mammalian Target of Rapamycin Pathway Markers in Lung Adenocarcinoma and Squamous Cell Carcinoma

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