The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer

Castañeda, Carlos A.; Cortés, Javier; Gómez, Henry L.; Ciruelos, Eva

doi:10.1007/s10555-010-9261-0

Cited by 156 publications

(136 citation statements)

References 112 publications

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“…AKT can regulate programmed cell death by inhibition of Fas ligand (FasL), BCL2-associated death promoter (BAD), BCL-2-interacting mediator of cell death (BIM), or BCL-2-associated X-protein (BAX), and degradation of p53. [20,21] Finally, either directly or indirectly, AKT regulates NF-kB (through IkB kinase), RAF, and c-JUN N-terminal kinase (JNK). [22] mTOR is a serine/threonine kinase that regulates cell growth, survival, and metabolism.…”

Section: Rapamycin (Mtor) Signaling Pathwaymentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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Section: Rapamycin (Mtor) Signaling Pathwaymentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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“…The assessment of the PI3K/AKT/mTOR pathway and its aberrant activation have been described in several human cancers, such as breast cancer, colorectal cancer, squamous cell carcinomas, angiosarcomas and soft tissue tumors (Castaneda et al 2010, Quesnelle et al 2007, Clark et al 2010, Lahat et al 2010, Dobashi et al 2009. After p53, the PI3K/AKT/mTOR is the most frequently activated pathway in neoplastic processes (Agarwal et al 2010).…”

Section: The Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

The importance of the PI3K/AKT/mTOR signaling pathway in canine neoplasms: Literature review

et al. 2016

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“…In eukaryotic cells, cell division or proliferation is a tightly controlled process driven by stimulators with fine tuning by inhibitors and feedback mechanisms (Lord, 1986;Kurzawa and Morris, 2010). Growth factors, cytokines and mitogens direct cells to enter the mitotic cycle and activate a cascade of signaling pathways including MAP kinase (MAPK) pathway (Tartaglia and Gelb, 2010), phosphatidyl inositol-3 kinase (PI3K)/AKT pathway (Castaneda et al, 2010) and JAK/STAT pathway (Spano et al, 2006;Borges et al, 2008). Dysregulation of these signaling pathways could result in aberrant cell proliferation as in the case of cancer (Kim and Choi, 2010).…”

Section: Er60 Protease and Breast Cancer Proliferationmentioning

confidence: 99%

Downregulation of ER60 Protease Inhibits Cellular Proliferation by Inducing G1/S Arrest in Breast Cancer Cells In Vitro

Lwin

Yip

Chew

et al. 2012

The Anatomical Record

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ER60 protease, a 58-kDa molecular chaperone in the endoplasmic reticulum, is involved in glycoprotein synthesis. ER60 protease has been reported to be differentially expressed in various cancers including breast carcinoma. This study explored the relationship of ER60 protease with cell proliferation in breast cancer in vitro. ER60 protease expression was first determined in a panel of breast cell lines by real-time RT-PCR and Western blot analysis and found to be most abundantly expressed in T47D breast cancer cells. The ER60 protease gene was then successfully knocked down in T47D breast cancer cells using two different sequences of small-interfering RNA. The silencing efficiencies of siER-1 and siER-2 at 48-hr post-transfection were found to be >80% at the mRNA level with concomitant downregulation of the ER60 protease protein by >60% when compared with control T47D breast cancer cells. Downregulation of ER60 protease was also associated with inhibition of cell proliferation when assessed by the AlamarBlue assay. Cell cycle analysis performed on the siER-1-and siER-2-transfected cells, revealed an increase in G1 phase population and a decrease in the S and G2/M phase populations compared with control cells, implicating G1/S cell cycle arrest. It would appear that ER60 protease is involved in breast tumorigenesis and could therefore be a prospective target for cancer therapeutics. Anat Rec, 295:410-416, 2012. V C 2012 Wiley Periodicals, Inc.

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The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer

Cited by 156 publications

References 112 publications

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

The importance of the PI3K/AKT/mTOR signaling pathway in canine neoplasms: Literature review

Downregulation of ER60 Protease Inhibits Cellular Proliferation by Inducing G1/S Arrest in Breast Cancer Cells In Vitro

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