Pathobiology 2010;77:289–300
(DOI:10.1159/000320936)

Alteration of REDD1-Mediated Mammalian Target of Rapamycin Pathway and Hypoxia-Inducible Factor-1α Regulation in Human Breast Cancer

Koo J.S. · Jung W.
Department of Pathology, Yonsei University Health System, Seoul, South Korea
email Corresponding Author


 goto top of outline Key Words

  • Hypoxia
  • REDD1
  • Mammalian target of rapamycin
  • Hypoxia-inducible factor-1α
  • Breast neoplasm

 goto top of outline Abstract

Objective: The purpose of this study is to investigate REDD1-(regulated in development and DNA damage response 1) mediated regulation of the mammalian target of rapamycin (mTOR) pathway in breast cancer. Methods: A tissue microarray included samples from 224 patients with breast cancer, and 30 patients with papilloma were used as a control group. An immunohistochemistry (IHC) including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epithelial growth factor receptor, cytokeratin 5/6, glucose transporter 1 (Glut-1), hypoxia-inducible factor (HIF)-1α, REDD1, AMPK (5′-adenosine-monophosphate-activated protein kinase) α1, 14-3-3σ, phosphatase and tensin homolog, phospho-Akt, phospho-mTOR, phospho-S6, and Ki-67 was conducted. The phenotypic classification of breast cancer was performed based on the results of the IHC for ER, PR and HER2: luminal A, luminal B, HER2 overexpression and triple-negative breast cancer (TNBC). Results: Glut-1 and HIF-1α were more highly expressed in TNBC, the HER2 overexpression type and papilloma than in the luminal A and B phenotypes (p = 0.000). REDD1 expression was higher in papilloma than in breast cancer (p = 0.000), but no difference was found among the 4 breast cancer phenotypes (p = 0.307). Conclusion: In the HER2 overexpression type and TNBC, tumor cell proliferation and survival in the hypoxic tumor environment could possibly be due to disinhibition of the mTOR pathway and HIF-1α stabilization by downregulation of REDD1.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D: Molecular portraits of human breast tumours. Nature 2000;406:747–752.
  2. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lønning P, Børresen-Dale AL: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98:10869–10874.
  3. Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale AL, Botstein D: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003;100:8418–8423.
  4. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET: Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 2003;100:10393–10398.
  5. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004;10:5367–5374.
  6. Rakha EA, Putti TC, Abd El-Rehim DM, Paish C, Green AR, Powe DG, Lee AH, Robertson JF, Ellis IO: Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 2006;208:495–506.
  7. Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, Nielsen TO, Foulkes WD: Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 2007;7:134.
  8. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM: Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006;19:264–271.
  9. Kim MJ, Ro JY, Ahn SH, Kim HH, Kim SB, Gong G: Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol 2006;37:1217–1226.
  10. Tsuda H, Takarabe T, Hasegawa F, Fukutomi T, Hirohashi S: Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. Am J Surg Pathol 2000;24:197–202.
  11. Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, Isola JJ: Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 1991;49:650–655.
  12. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME, King CR: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 1990;8:103–112.
  13. Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, Feinstein E: Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol 2002;22:2283–2293.
  14. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18:2893–2904.
  15. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW: Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008;22:239–251.
  16. Reiling JH, Hafen E: The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 2004;18:2879–2892.
  17. Sofer A, Lei K, Johannessen CM, Ellisen LW: Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 2005;25:5834–5845.
  18. Schneider A, Younis RH, Gutkind JS: Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia 2008;10:1295–1302.
  19. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. 1. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403–410.
  20. Cutler SJ, Black MM, Mork T, Harvei S, Freeman C: Further observations on prognostic factors in cancer of the female breast. Cancer 1969;24:653–667.
  21. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–145.
  22. Brenton JD, Carey LA, Ahmed AA, Caldas C: Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 2005;23:7350–7360.
  23. Schnitt SJ, Collins LC: Biopsy interpretation of the breast, ed 1. New York, Lippincott Williams and Wilkins, 2009.
  24. Jin HO, An S, Lee HC, Woo SH, Seo SK, Choe TB, Yoo DH, Lee SB, Um HD, Lee SJ, Park MJ, Kim JI, Hong SI, Rhee CH, Park IC: Hypoxic condition- and high cell density-induced expression of Redd1 is regulated by activation of hypoxia-inducible factor-1α and Sp1 through the phosphatidylinositol 3-kinase/Akt signaling pathway. Cell Signal 2007;19:1393–1403.
  25. Katiyar S, Liu E, Knutzen CA, Lang ES, Lombardo CR, Sankar S, Toth JI, Petroski MD, Ronai Z, Chiang GG: REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase. EMBO Rep 2009;10:866–872.
  26. Horak P, Crawford AR, Vadysirisack DD, Nash ZM, DeYoung MP, Sgroi D, Ellisen LW: Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis. Proc Natl Acad Sci USA 2010;107:4675–4680.
  27. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E: Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node-negative breast carcinoma. Cancer 2003;97:1573–1581.
  28. Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G: Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 2002;8:1831–1837.
  29. Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J, Berra E: HIF-1α and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 2007;120:1451–1458.
  30. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL: HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001;21:3995–4004.

 goto top of outline Author Contacts

Dr. Woohee Jung, MD, PhD
Department of Pathology, Yonsei University Health System
Gangnam Severance Hospital
612 Eonjuro Gangnam-gu, Seoul 135-720 (South Korea)
Tel. +82 2 2019 3541, Fax +82 2 3463 2103, E-Mail Jungwh96@yuhs.ac


 goto top of outline Article Information

Received: June 28, 2010
Accepted after revision: September 3, 2010
Published online: January 24, 2011
Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 6, Number of References : 30


 goto top of outline Publication Details

Pathobiology (Exploring the basis of disease)

Vol. 77, No. 6, Year 2010 (Cover Date: January 2011)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015-2008 (Print), eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.