Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers

Zhou, Xiaoyan; Tan, Ming; Hawthorne, Valerie Stone; Klos, Kristine S.; Lan, Keng Hsueh; Yang, Ying; Yang, Wentao; Smith, Terry L.; Shi, Daren; Yu, Dihua

doi:10.1158/1078-0432.ccr-04-0112

Cited by 285 publications

(286 citation statements)

References 41 publications

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“…It is postulated that this may result from activation of other upstream regulators, such as amplification of growth factor receptors. Zhou et al, 28 in a study of 165 invasive breast cancers, noted a positive association between phosphorylated Akt and Her2/neu expression, while Panigrahi et al 25 noted a positive significant correlation of p-AKT with ER in their series of cases and therefore suggest that ER, rather than PTEN or Her2, is the upstream regulator. We did not observe either of these correlations.…”

Section: Discussionmentioning

confidence: 96%

The Akt pathway in human breast cancer: a tissue-array-based analysis

et al. 2006

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The Akt pathway, an important regulator of cell proliferation and survival, is deregulated in many cancers. The pathway has achieved considerable importance due to the development of kinase inhibitors that are able to successfully reduce tumor growth. This study was conducted to determine the status of the Akt pathway in human breast cancers and to study the relationship between the different component proteins. Expression levels of PTEN, phosphorylated forms of the constituent proteins (Akt, FKHR, mTOR, and S6) and cyclin D1 were evaluated by immunohistochemistry, on consecutive sections from a tissue microarray containing 145 invasive breast cancers and 140 pure ductal carcinomas in-situ. Aberrant expression was correlated statistically with tumor characteristics and disease outcome. The Akt pathway was found to be activated early in breast cancer, in the in-situ stage. In all, 33, 15, 32, and 60% of ductal carcinoma in-situ showed overexpression of Akt, FKHR, mTOR, and cyclin D1. PTEN loss did not correlate statistically with expression of AKT or any of the other proteins with the exception of S6, indicating that Akt activation was not a result of PTEN loss. Expression levels of PTEN and S6 were significantly different in in-situ and invasive cancers, indicating association with disease progression. Loss of PTEN was noted in 11% of in-situ as compared to 26% of invasive cancers, while S6 overexpression was seen in 47% in-situ and in 72% invasive cancers. High-grade carcinomas were associated with PTEN loss, while low-grade carcinomas with good prognostic features showed cyclin D1 overexpression and were associated with longer disease free survival. Additionally, cancers with mTOR overexpression showed a three times greater risk for disease recurrence. Overall, a large proportion of in-situ and invasive breast cancers overexpressed cyclinD1 and S6. Our results may have significant implications in the development and application of targeted therapy.

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Section: Discussionmentioning

confidence: 96%

The Akt pathway in human breast cancer: a tissue-array-based analysis

et al. 2006

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“…Phosphorylation at both threonine 308 and serine 473 are required for the activation of AKT. Elevation of AKT phosphorylation may be due to any activation of upstream protein kinase receptor Her2 or EGFR which activates AKT via PDK-1 in RMS (Zhou et al, 2004). In addition, reduction in activity of the negative regulator of AKT signalling, such as PTEN, might also contribute to the elevation of p-AKT.…”

Section: Discussionmentioning

confidence: 99%

PDK-1/AKT pathway as a novel therapeutic target in rhabdomyosarcoma cells using OSU-03012 compound

et al. 2007

Br J Cancer

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Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma including two major subtypes, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Increasing evidence suggests that oncogenesis of RMS involves multistages of signalling protein dysregulation which may include prolonged activation of serine/threonine kinases such as phosphoinositide-dependant kinase-1 (PDK-1) and AKT. To date, whether PDK-1/AKT pathway is activated in RMS is unknown. This study was to examine phosphorylation status of AKT and to evaluate a novel small molecular inhibitor, OSU-03012 targeting PDK-1 in RMS. We examined phosphorylation levels of AKT using ARMS and ERMS tissue microarray and immunohistochemistry staining. Our results showed phospho-AKT Thr308 level is elevated 42 and 35% in ARMS and ERMS, respectively. Phospho-AKT Ser473 level is also increased 43% in ARMS and 55% in ERMS. Furthermore, we showed that OSU-03012 inhibits cell viability and induces apoptosis in ARMS and ERMS cell lines (RH30, SMS-CTR), which express elevated phospho-AKT levels. Normal cells are much less sensitive to OSU-03012 and in which no detectable apoptosis was observed. This study showed, for the first time, that PDK-1/AKT pathway is activated in RMS and may play an important role in survival of RMS. PDK-1/AKT pathway may be an attractive therapeutic target for cancer intervention in RMS using OSU-03012.

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“…We and others (Guy et al, 1992;Tan et al, 1997Tan et al, , 2005Tan et al, , 2006aTan et al, , 2006b) have previously shown that the overexpression of ErbB2 increases the transformation and/ or metastatic potentials of breast cancer cells. In addition, ErbB2 has been shown to activate signaling molecules that regulate bioenergetic metabolism, such as Ras, PI3K/Akt, mTOR and Src (Yarden and Sliwkowski, 2001;Zhou et al, 2004;Tan et al, 2005Tan et al, , 2006bZhang et al, 2007). A recent study investigated the role of lactate dehydrogenase A (LDH-A), a critical enzyme in the glycolysis pathway, in the tumor maintenance of neu-transformed mouse mammary epithelial cells, showing that compared to normal cells, cancer cells have deregulated bioenergetic metabolism and increased glycolysis (Fantin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

et al. 2009

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ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

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Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers

Cited by 285 publications

References 41 publications

The Akt pathway in human breast cancer: a tissue-array-based analysis

The Akt pathway in human breast cancer: a tissue-array-based analysis

PDK-1/AKT pathway as a novel therapeutic target in rhabdomyosarcoma cells using OSU-03012 compound

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

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