Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma

Tomita, Yoshihiro; Morooka, Takaya; Hoshida, Yoshihiko; Zhang, Binglin; Qiu, Ying; Nakamichi, Itsuko; Hamada, Kenichiro; Ueda, Takafumi; Naka, Norifumi; Kudawara, Ikuo; Aozasa, Katsuyuki

doi:10.1158/1078-0432.ccr-05-1732

Cited by 57 publications

(53 citation statements)

References 36 publications

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“…Although FOXO1A is generally regarded as a direct substrate of AKT1, 16 it remains controversial 26 and soft tissue sarcoma, 27 while no association was observed in prostate cancer 15 and in breast cancer. 13 The present study showed a positive correlation between the expression of pFOXO1A and that of pAKT1 (Po0.001).…”

Section: Discussionmentioning

confidence: 99%

Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer

Kim

Lee

et al. 2007

Modern Pathology

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Increased phosphorylation of FOXO1A, a FOXO transcription factor, has been implicated in several human cancers; however, it has not been studied in the gastric cancer to date. To determine the status of pFOXO1A expression in human gastric cancers and to determine its relationship with other tumor-associated proteins, we performed immunohistochemical staining on tissue array slides containing 272 human gastric carcinoma specimens. In non-neoplastic gastric mucosa, the expression of pFOXO1A was observed primarily in cells in the proliferative zone and in areas of intestinal metaplasia. In gastric carcinomas, the expression of pFOXO1A was observed in 230 (84.6%) out of 272 cases examined, and was positively correlated with the Ki-67-labeling index (P ¼ 0.026). The expression of pFOXO1A was higher in the early stages of pTNM (Po0.001), and was inversely correlated with the intestinal type by Lauren's classification (P ¼ 0.001), lymphatic invasion (P ¼ 0.017) and lymph node metastasis (Po0.001). Moreover, the expression of pFOXO1A was correlated with a longer patient survival (P ¼ 0.004). In addition, the expression of pFOXO1A was correlated with that of pAKT1 (Po0.001), PTEN (P ¼ 0.009), CDKN2A (P ¼ 0.012), APC (P ¼ 0.048), SMAD4 (Po0.001), CD82 (P ¼ 0.011), and BCL2 (P ¼ 0.011). In conclusion, our results showed that the expression of pFOXO1A is a frequent and early event in gastric tumorigenesis and that there is a significant correlation between pFOXO1A and better prognosis. Thus, our data suggest that the expression of pFOXO1A may serve as a valuable prognostic variable in gastric carcinoma and have significant implications for the development and application of targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer

Kim

Lee

et al. 2007

Modern Pathology

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“…3,5 However, the expression profiles of the molecules along the Akt/mTOR pathway have been analyzed in a relatively small number of clinical materials. 5,13,14 Some authors investigated Akt/mTOR pathway involvement in STS series and demonstrated a correlation between Akt activation and a worse prognosis 15 or a greater probability of metastasis 13 ; whereas, to our knowledge, no investigations have focused on SS as a single entity, and the prognostic impact of this pathway on SS has remained to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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BACKGROUND:The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit a (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

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“…It is well established that constitutive activation of Akt, through PI3K amplification or PTEN mutation, contributes to the oncogenic process and is associated with a poor prognosis and resistance to chemo-and radio-therapy (94). Indeed, Akt activation is one of the most frequent molecular alterations in cancers, including melanoma, gastric, pancreatic, breast, sarcoma and prostate cancer (95)(96)(97)(98). While there are instances where the three Akt isoforms are able to compensate for each other, recent research show that their tissue expression patterns and functions are different (99,100).…”

Section: Phosphatidylinositol 3-kinase/protein Kinase B (Pi3k/akt) Simentioning

confidence: 99%

The T-Box transcription factor 3 in development and cancer

Willmer

Cooper

Peres

et al. 2017

BST

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Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma

Cited by 57 publications

References 36 publications

Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer

Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

The T-Box transcription factor 3 in development and cancer

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