Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2

Hong, Liu; Radisky, Derek C.; Nelson, Celeste M.; Zhang, Hui; Fata, Jimmie E.; Roth, Richard A.; Bissell, Mina J.

doi:10.1073/pnas.0511342103

Cited by 184 publications

(173 citation statements)

References 71 publications

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“…Indeed, these data fit with studies by Bissel et al showing that hyperactivation of Akt 1 can prevent the invasive behavior underlying breast metastasis. It is suggested that Akt phosphorylation in breast cancer cells induces phosphorylation of the tumor suppressor tuberous sclerosis complex 2, leading to reduced focal adhesions, migration motility, and invasion (51). This is in agreement with the analyses of the double-transgenic ErbB2/ PKB mouse model for tumor metastasis in which metastatic lesions in lung are found only in the ErbB2 transgenes.…”

Section: Discussionsupporting

confidence: 77%

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Salah

Maoz

Pokroy

et al. 2007

Molecular Cancer Research

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Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase -mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell -derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracyclineinducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim EL induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim EL , a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. (Mol Cancer Res 2007;5(3):229 -40)

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Section: Discussionsupporting

confidence: 77%

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Salah

Maoz

Pokroy

et al. 2007

Molecular Cancer Research

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“…This last may reflect the striking amount of active AKT in the BT-20 line; AKT activity is increased in both cell lines after MUC1 siRNA, which disagrees with the findings of previous work in 3Y1 fibroblasts [23]. Recent studies have emphasized the complex and context-specific regulation of even such classical oncogenes as AKT [33]. The differences between the two breast cancer cell lines in this study suggest that MUC1 oncogenic functions are also subject to cell-specific regulation, and stress the need for understanding the cellular signaling context when interpreting results.…”

Section: Resultscontrasting

confidence: 56%

“…20 However, it is vital to always bear in mind the fact that these studies are conducted on established cell lines in two-dimensional culture. A recent paper from the Bissell group 33 highlights the importance of cellular context in understanding protein function: the report outlines an anti-metastatic effect for the well-characterized oncogene AKT, and emphasizes that understanding a complex network of cellular signaling events is essential in drawing conclusions about the role of any one protein in the process of oncogenesis. Therefore, it is quite likely that these results largely reflect cell-specific differences between the cell lines used, as MUC1 has been characterized as an oncogene by its overexpression in the mouse mammary gland.…”

Section: Introductionmentioning

confidence: 99%

Interaction of the MUC1 Tumor Antigen and the Adenomatous Polyposis Coli Tumor Suppressor in Human Breast Cancer

Hattrup¹,

Gendler²,

Hansson³

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 5e. TASK NUMBER 5f. WORK UNIT NUMBER REPORT DATE 01-03-2006 REPORT TYPE Annual Summary DATES COVERED23 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERMayo Clinic Scottsdale, AZ 85259 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTESOriginal contains colored plates: ALL DTIC reproductions will be in black and white. ABSTRACTThis project was designed to analyze the effect of MUC1 and APC on two important signaling pathways in breast cancer, those mediated by β-catenin and the ErbB kinases. We present herein results indicating that loss of MUC1 corresponds to decreased total β-catenin levels in breast cancer cells; as this is accompanied by a reduction in the amount of β-catenin that lacks GSK3β-mediated phosphorylation, the destabilization of β-catenin after MUC1 loss occurs at least in part through the APC/GSK3β destruction complex. We also show that another APC-dependent pathway involving p53 might participate as well, since MUC1 loss correlates to increased p53 levels. Finally, we show that loss of MUC1 alters β-catenin dependent transcription, as well as demonstrating a novel link between expression of MUC1 and transcription of members of the ERK pathway downstream of the ErbB kinases. These transcriptional changes are correlated to alterations in oncogenic events, further supporting the idea that MUC1 and APC are integral factors in regulation of signaling in breast cancer. These findings add to the growing understanding of how the oncoprotein MUC1 alters breast cancer signaling, specifically in relationship to the APC tumor suppressor. SUBJECT TERMS IntroductionThis project was designed to study the interaction between the MUC1 oncoprotein and the adenomatous polyposis coli (APC) tumor suppressor in human breast cancer. MUC1 has long been known to play an important role in breast cancer, first as a tumor antig...

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“…TSC2 diminished the anti-invasive actions of AKT1 in breast cancer cells, apparently acting as a tumor promoter under these conditions (61). Thus, the cellular milieu in which AKT is activated determines cell fate.…”

Section: Breastmentioning

confidence: 99%

Targeting the AKT protein kinase for cancer chemoprevention

Crowell

Steele

Fay

2007

Molecular Cancer Therapeutics

149

114

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The AKT protein kinase transduces signals from growth factors and oncogenes to downstream targets that control crucial elements in tumor development. The AKT pathway is one of the most frequently hyperactivated signaling pathways in human cancers. Available data are reviewed herein to support targeting the AKT kinase for cancer prevention. This review will present data to show that AKT is up-regulated in preneoplastic lesions across a broad range of target tissues, briefly describe drug development efforts in this area, and present evidence that downregulation of AKT signaling may be a viable strategy to prevent cancer.

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Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2

Cited by 184 publications

References 71 publications

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Interaction of the MUC1 Tumor Antigen and the Adenomatous Polyposis Coli Tumor Suppressor in Human Breast Cancer

Targeting the AKT protein kinase for cancer chemoprevention

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