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Breast Cancer Research
Published in: Breast Cancer Research 5/2013

Open Access 01-10-2013 | Research article

The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials

Authors: Elin Karlsson, Gizeh Pérez-Tenorio, Risul Amin, Josefine Bostner, Lambert Skoog, Tommy Fornander, Dennis C Sgroi, Bo Nordenskjöld, Anna-Lotta Hallbeck, Olle Stål

Published in: Breast Cancer Research | Issue 5/2013

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Abstract

Introduction

mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.

Methods

The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.

Results

S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.

Conclusion

This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.
Appendix
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Literature
1.
Musgrove EA, Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009, 9: 631-643. 10.1038/nrc2713.CrossRefPubMed
2.
3.
Miller TW, Balko JM, Arteaga CL: Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011, 29: 4452-4461. 10.1200/JCO.2010.34.4879.CrossRefPubMedPubMedCentral
4.
Villarreal-Garza C, Cortes J, Andre F, Verma S: mTOR inhibitors in the management of hormone receptor-positive breast cancer: the latest evidence and future directions. Ann Oncol. 2012, 23: 2526-2535. 10.1093/annonc/mds075.CrossRefPubMed
5.
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012, 366: 520-529. 10.1056/NEJMoa1109653.CrossRefPubMed
6.
Lyzogubov V, Khozhaenko Y, Usenko V, Antonjuk S, Ovcharenko G, Tikhonkova I, Filonenko V: Immunohistochemical analysis of Ki-67, PCNA and S6K1/2 expression in human breast cancer. Exp Oncol. 2005, 27: 141-144.PubMed
7.
Couch FJ, Wang XY, Wu GJ, Qian J, Jenkins RB, James CD: Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res. 1999, 59: 1408-1411.PubMed
8.
Perez-Tenorio G, Karlsson E, Waltersson MA, Olsson B, Holmlund B, Nordenskjöld B, Fornander T, Skoog L, Stål O: Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Res Treat. 2011, 128: 713-723. 10.1007/s10549-010-1058-x.CrossRefPubMed
9.
van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002, 347: 1999-2009. 10.1056/NEJMoa021967.CrossRefPubMed
10.
Armengol G, Rojo F, Castellvi J, Iglesias C, Cuatrecasas M, Pons B, Baselga J: Ramon y Cajal S: 4E-binding protein 1: a key molecular 'funnel factor’ in human cancer with clinical implications. Cancer Res. 2007, 67: 7551-7555. 10.1158/0008-5472.CAN-07-0881.CrossRefPubMed
11.
Karlsson E, Waltersson MA, Bostner J, Perez-Tenorio G, Olsson B, Hallbeck AL, Stål O: High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1. Genes Chromosomes Cancer. 2011, 50: 775-787. 10.1002/gcc.20900.CrossRefPubMed
12.
Wang L, Rhodes CJ, Lawrence JC: Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex 1. J Biol Chem. 2006, 281: 24293-24303. 10.1074/jbc.M603566200.CrossRefPubMed
13.
Ma XM, Yoon SO, Richardson CJ, Julich K, Blenis J: SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell. 2008, 133: 303-313. 10.1016/j.cell.2008.02.031.CrossRefPubMed
14.
Bachmann RA, Kim JH, Wu AL, Park IH, Chen J: A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem. 2006, 281: 7357-7363. 10.1074/jbc.M512218200.CrossRefPubMed
15.
Goh ET, Pardo OE, Michael N, Niewiarowski A, Totty N, Volkova D, Tsaneva IR, Seckl MJ, Gout I: Involvement of heterogeneous ribonucleoprotein F in the regulation of cell proliferation via the mammalian target of rapamycin/S6 kinase 2 pathway. J Biol Chem. 2010, 285: 17065-17076. 10.1074/jbc.M109.078782.CrossRefPubMedPubMedCentral
16.
Rong L, Livingstone M, Sukarieh R, Petroulakis E, Gingras AC, Crosby K, Smith B, Polakiewicz RD, Pelletier J, Ferraiuolo MA, Sonenburg N: Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs. RNA. 2008, 14: 1318-1327. 10.1261/rna.950608.CrossRefPubMedPubMedCentral
17.
Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK: S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009, 284: 6361-6369.CrossRefPubMed
18.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM: Statistics Subcommittee of NCIEWGoCD: REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat. 2006, 100: 229-235. 10.1007/s10549-006-9242-8.CrossRefPubMed
19.
Rutqvist LE, Johansson H: Long-term follow-up of the Stockholm randomized trials of postoperative radiation therapy versus adjuvant chemotherapy among 'high risk’ pre- and postmenopausal breast cancer patients. Acta Oncol. 2006, 45: 517-527. 10.1080/02841860600702068.CrossRefPubMed
20.
Rutqvist LE, Johansson H: Stockholm Breast Cancer Study G: Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer. Acta Oncol. 2007, 46: 133-145. 10.1080/02841860601034834.CrossRefPubMed
21.
Gomez-Abad C, Pisonero H, Blanco-Aparicio C, Roncador G, Gonzalez-Menchen A, Martinez-Climent JA, Mata E, Rodriguez ME, Munoz-Gonzalez G, Sanchez-Beato M, Leal JF, Bischoff JR, Piris MA: PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma. Blood. 2011, 118: 5517-5527. 10.1182/blood-2011-03-344374.CrossRefPubMed
22.
Jerevall PL, Ma XJ, Li H, Salunga R, Kesty NC, Erlander MG, Sgroi DC, Holmlund B, Skoog L, Fornander T, Nordenskjöld B, Stål O: Prognostic utility of HOXB13:IL17BR and molecular grade index in early-stage breast cancer patients from the Stockholm trial. Br J Cancer. 2011, 104: 1762-1769. 10.1038/bjc.2011.145.CrossRefPubMedPubMedCentral
23.
Khoshnoud MR, Löfdahl B, Fohlin H, Fornander T, Stål O, Skoog L, Bergh J, Nordenskjöld B: Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen. Breast Cancer Res Treat. 2011, 126: 421-430. 10.1007/s10549-010-1202-7.CrossRefPubMed
24.
Stål O, Sullivan S, Sun XF, Wingren S, Nordenskjöld B: Simultaneous analysis of c-erbB-2 expression and DNA content in breast cancer using flow cytometry. Cytometry. 1994, 16: 160-168. 10.1002/cyto.990160210.CrossRefPubMed
25.
Gunnarsson C, Ahnström M, Kirschner K, Olsson B, Nordenskjöld B, Rutqvist LE, Skoog L, Stål O: Amplification of HSD17B1 and ERBB2 in primary breast cancer. Oncogene. 2003, 22: 34-40. 10.1038/sj.onc.1206078.CrossRefPubMed
26.
Jansson A, Delander L, Gunnarsson C, Fornander T, Skoog L, Nordenskjöld B, Stål O: Ratio of 17HSD1 to 17HSD2 protein expression predicts the outcome of tamoxifen treatment in postmenopausal breast cancer patients. Clin Cancer Res. 2009, 15: 3610-3616. 10.1158/1078-0432.CCR-08-2599.CrossRefPubMed
27.
Stål O, Sullivan S, Wingren S, Skoog L, Rutqvist LE, Carstensen JM: Nordenskjöld B: c-erbB-2 expression and benefit from adjuvant chemotherapy and radiotherapy of breast cancer. Eur J Cancer. 1995, 31A: 2185-2190.CrossRefPubMed
28.
Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjöld B, Rutqvist LE, Skoog L, Stål O: PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 2007, 13: 3577-3584. 10.1158/1078-0432.CCR-06-1609.CrossRefPubMed
29.
Stål O, Perez-Tenorio G, Åkerberg L, Olsson B, Nordenskjöld B, Skoog L, Rutqvist LE: Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 2003, 5: R37-R44. 10.1186/bcr569.CrossRefPubMedPubMedCentral
30.
Bostner J, Karlsson E, Pandiyan MJ, Westman H, Skoog L, Fornander T, Nordenskjold B, Stal O: Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Res Treat. 2012, 137: 397-406.CrossRefPubMedPubMedCentral
31.
32.
Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J: An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A. 2005, 102: 13550-13555. 10.1073/pnas.0506230102.CrossRefPubMedPubMedCentral
33.
Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, Liu ET, Miller L, Nordgren H, Ploner A, Sandelin K, Shaw PM, Smeds J, Skoog L, Wedrén S, Bergh J: Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 2005, 7: R953-R964. 10.1186/bcr1325.CrossRefPubMedPubMedCentral
34.
Filonenko VV, Tytarenko R, Azatjan SK, Savinska LO, Gaydar YA, Gout IT, Usenko VS, Lyzogubov VV: Immunohistochemical analysis of S6K1 and S6K2 localization in human breast tumors. Exp Oncol. 2004, 26: 294-299.PubMed
35.
Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-Gonzalez S, Holz MK: Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene. 2012, 31: 5073-5080. 10.1038/onc.2011.657.CrossRefPubMedPubMedCentral
36.
Benavente S, Verges R, Hermosilla E, Fumanal V, Casanova N, Garcia A, Ramon YCS, Giralt J: Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2009, 75: 1316-1322. 10.1016/j.ijrobp.2009.01.004.CrossRefPubMed
37.
Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J: Ramon y Cajal S: Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer. 2006, 107: 1801-1811. 10.1002/cncr.22195.CrossRefPubMed
38.
O'Reilly KE, Warycha M, Davies MA, Rodrik V, Zhou XK, Yee H, Polsky D, Pavlick AC, Rosen N, Bhardwaj N, Mills G, Osman I: Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res. 2009, 15: 2872-2878. 10.1158/1078-0432.CCR-08-2336.CrossRefPubMedPubMedCentral
39.
Rojo F, Najera L, Lirola J, Jimenez J, Guzman M, Sabadell MD, Baselga J: Ramon y Cajal S: 4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis. Clin Cancer Res. 2007, 13: 81-89. 10.1158/1078-0432.CCR-06-1560.CrossRefPubMed
40.
Balakumaran BS, Porrello A, Hsu DS, Glover W, Foye A, Leung JY, Sullivan BA, Hahn WC, Loda M, Febbo PG: MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy. Cancer Res. 2009, 69: 7803-7810. 10.1158/0008-5472.CAN-09-0910.CrossRefPubMedPubMedCentral
41.
Vogel C, Marcotte EM: Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012, 13: 227-232.PubMedPubMedCentral
42.
Copp J, Manning G, Hunter T: TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res. 2009, 69: 1821-1827. 10.1158/0008-5472.CAN-08-3014.CrossRefPubMedPubMedCentral
43.
Nawroth R, Stellwagen F, Schulz WA, Stoehr R, Hartmann A, Krause BJ, Gschwend JE, Retz M: S6K1 and 4E-BP1 are independent regulated and control cellular growth in bladder cancer. PLoS One. 2011, 6: e27509-10.1371/journal.pone.0027509.CrossRefPubMedPubMedCentral
44.
Zhang Y, Zheng XF: mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors. Cell Cycle. 2012, 11: 594-603. 10.4161/cc.11.3.19096.CrossRefPubMedPubMedCentral
45.
Rennefahrt UE, Deacon SW, Parker SA, Devarajan K, Beeser A, Chernoff J, Knapp S, Turk BE, Peterson JR: Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J Biol Chem. 2007, 282: 15667-15678. 10.1074/jbc.M700253200.CrossRefPubMed
46.
Riaz A, Zeller KS, Johansson S: Receptor-specific mechanisms regulate phosphorylation of AKT at Ser473: role of RICTOR in β1 integrin-mediated cell survival. PLoS One. 2012, 7: e32081-10.1371/journal.pone.0032081.CrossRefPubMedPubMedCentral
47.
Meric-Bernstam F, Chen H, Akcakanat A, Do KA, Lluch A, Hennessy BT, Hortobagyi GN, Mills GB, Gonzalez-Angulo AM: Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. Breast Cancer Res. 2012, 14: R138-10.1186/bcr3343.CrossRefPubMedPubMedCentral
48.
Obr AE, Edwards DP: The biology of progesterone receptor in the normal mammary gland and in breast cancer. Mol Cell Endocrinol. 2012, 357: 4-17. 10.1016/j.mce.2011.10.030.CrossRefPubMed
49.
Wood CE, Register TC, Cline JM: Transcriptional profiles of progestogen effects in the postmenopausal breast. Breast Cancer Res Treat. 2009, 114: 233-242. 10.1007/s10549-008-0003-8.CrossRefPubMed
Metadata
Title
The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials
Authors
Elin Karlsson
Gizeh Pérez-Tenorio
Risul Amin
Josefine Bostner
Lambert Skoog
Tommy Fornander
Dennis C Sgroi
Bo Nordenskjöld
Anna-Lotta Hallbeck
Olle Stål
Publication date
01-10-2013
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2013
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3557

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