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Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.07.2009 | Original Paper

Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro

verfasst von: Silvia Darb-Esfahani, Areeg Faggad, Aurelia Noske, Wilko Weichert, Ann-Christin Buckendahl, Berit Müller, Jan Budczies, Annika Röske, Manfred Dietel, Carsten Denkert

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 7/2009

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Abstract

Purpose

Endometrial adenocarcinoma, due to a frequent activation of PI3 K/AKT has been proposed as a candidate neoplasm for the treatment with mTOR inhibitors. Yet, data on the expression of mTOR cascade components in endometrial cancer are lacking.

Methods

To provide a basis for futher studies with mTOR inhibitors, we used immunohistochemistry to evaluate the expression of activated mTOR pathway components in 57 endometrial cancer surgical specimens in vivo, and investigated in vitro the relation between the activation of AKT/mTOR and the response to rapamycin.

Results

p-mTOR expression was associated with nuclear p-4EBP1 expression (P = 0.02), and was more frequent in tumors extending ouside the uterine corpus (P = 0.011). Nuclear p-4EBP1 expression was increased in carcinomas of poor differentiation (P = 0.012). In cultivated PTEN-deficient Ishikawa cells, in addition to an activation of AKT, a phosphorylation of mTOR and 4EBP1 was evident, while PTEN-wild type HEC-1A cells lacked AKT activation but revealed a reduced expression of p-mTOR and p-4EBP1. Rapamycin induced a growth reduction, which was clearly more pronounced in Ishikawa cells than in HEC-1A cells (P < 0.03) and could be observed for up to 6 days.

Conclusisons

Expression of mTOR and 4EBP1 characterize high-grade, high-stage endometrial adenocarcinomas and might be predictive markers of a response to rapamycin. Based on our results, we suggest that the expression of elements of the mTOR pathway in human tumor tissue should be further evaluated as a possible predictive marker in large-scale clinical studies as well as translational research protocols in clinical studies with mTOR inhibitors.

Armengol G, Rojo F, Castellvi J et al (2007) 4E-binding protein 1: a key molecular “funnel factor” in human cancer with clinical implications. Cancer Res 67:7551–7555. doi:10.1158/0008-5472.CAN-07-0881 PubMedCrossRef

Bae-Jump VL, Zhou C, Gehrig PA, Whang YE, Boggess JF (2006) Rapamycin inhibits hTERT telomerase mRNA expression, independent of cell cycle arrest. Gynecol Oncol 100:487–494. doi:10.1016/j.ygyno.2005.08.053 PubMedCrossRef

Bayascas JR, Alessi DR (2005) Regulation of Akt/PKB Ser473 phosphorylation. Mol Cell 18:143–145. doi:10.1016/j.molcel.2005.03.020 PubMedCrossRef

Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J, Ramon y Cajal S (2006) Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 107:1801–1811. doi:10.1002/cncr.22195 PubMedCrossRef

Chow LM, Baker SJ (2006) PTEN function in normal and neoplastic growth. Cancer Lett 241:184–196. doi:10.1016/j.canlet.2005.11.042 PubMedCrossRef

Culjkovic B, Topisirovic I, Borden KL (2007) Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E. Cell Cycle 6:65–69PubMed

Dudkin L, Dilling MB, Cheshire PJ et al (2001) Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758–1764PubMed

Easton JB, Houghton PJ (2006) mTOR and cancer therapy. Oncogene 25:6436–6446. doi:10.1038/sj.onc.1209886 PubMedCrossRef

Gadducci A, Cosio S, Genazzani AR (2006) Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies. Crit Rev Oncol Hematol 58:242–256. doi:10.1016/j.critrevonc.2005.11.002 PubMedCrossRef

Gao N, Flynn DC, Zhang Z et al (2004) G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3 K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am J Physiol Cell Physiol 287:C281–C291. doi:10.1152/ajpcell.00422.2003 PubMedCrossRef

Hecht JL, Mutter GL (2006) Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol 24:4783–4791. doi:10.1200/JCO.2006.06.7173 PubMedCrossRef

Herberger B, Puhalla H, Lehnert M et al (2007) Activated mammalian target of rapamycin is an adverse prognostic factor in patients with biliary tract adenocarcinoma. Clin Cancer Res 13:4795–4799. doi:10.1158/1078-0432.CCR-07-0738 PubMedCrossRef

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66PubMedCrossRef

Kanamori Y, Kigawa J, Itamochi H et al (2001) Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res 7:892–895PubMed

Kremer CL, Klein RR, Mendelson J et al (2006) Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate 66:1203–1212. doi:10.1002/pros.20410 PubMedCrossRef

Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344:427–431. doi:10.1042/0264-6021:3440427 PubMedCrossRef

Oda K, Stokoe D, Taketani Y, McCormick F (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65:10669–10673. doi:10.1158/0008-5472.CAN-05-2620 PubMedCrossRef

Pectasides D, Pectasides E, Economopoulos T (2007) Systemic therapy in metastatic or recurrent endometrial cancer. Cancer Treat Rev 33:177–190. doi:10.1016/j.ctrv.2006.10.007 PubMedCrossRef

Prat J (2004) Prognostic parameters of endometrial carcinoma. Hum Pathol 35:649–662. doi:10.1016/j.humpath.2004.02.007 PubMedCrossRef

Rojo F, Najera L, Lirola J et al (2007) 4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis. Clin Cancer Res 13:81–89. doi:10.1158/1078-0432.CCR-06-1560 PubMedCrossRef

Rowinsky EK (2004) Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 16:564–575. doi:10.1097/01.cco.0000143964.74936.d1 PubMedCrossRef

Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734. doi:10.1038/nrc1974 PubMedCrossRef

Steiner E, Eicher O, Sagemuller J et al (2003) Multivariate independent prognostic factors in endometrial carcinoma: a clinicopathologic study in 181 patients: 10 years experience at the Department of Obstetrics and Gynecology of the Mainz University. Int J Gynecol Cancer 13:197–203. doi:10.1046/j.1525-1438.2003.13021.x PubMedCrossRef

Tavassoli FA, Devilee P (2003) World Health Organization classification of tumours: tumours of the breast and the female genital organs. IARC Press, Lyon

Treeck O, Wackwitz B, Haus U, Ortmann O (2006) Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol Oncol 102:292–299. doi:10.1016/j.ygyno.2005.12.019 PubMedCrossRef

Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484. doi:10.1016/j.cell.2006.01.016 PubMedCrossRef

Zhou C, Gehrig PA, Whang YE, Boggess JF (2003) Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Mol Cancer Ther 2:789–795PubMed

Zhou X, Tan M, Stone Hawthorne V et al (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10:6779–6788. doi:10.1158/1078-0432.CCR-04-0112 PubMedCrossRef

Titel: Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro
verfasst von: Silvia Darb-Esfahani
Areeg Faggad
Aurelia Noske
Wilko Weichert
Ann-Christin Buckendahl
Berit Müller
Jan Budczies
Annika Röske
Manfred Dietel
Carsten Denkert
Publikationsdatum: 01.07.2009
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 7/2009
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-008-0529-5

Springer Medizin

Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro