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Integrated Quantitative Analysis of the Phosphoproteome and Transcriptome in Tamoxifen-resistant Breast Cancer*

  • Masaaki Oyama
    Correspondence
    To whom correspondence may be addressed: 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel.: 81-3-5449-5469; Fax: 81-3-5449-5491;
    Footnotes
    Affiliations
    From the Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,
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  • Takeshi Nagashima
    Footnotes
    Affiliations
    the Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan,
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  • Takashi Suzuki
    Affiliations
    Departments of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8578, Japan,
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  • Hiroko Kozuka-Hata
    Affiliations
    From the Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,
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  • Noriko Yumoto
    Affiliations
    the Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan,
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  • Yuichi Shiraishi
    Affiliations
    the Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan,
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  • Kazuhiro Ikeda
    Affiliations
    the Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan,
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  • Yoko Kuroki
    Affiliations
    the Computational Systems Biology Research Group, RIKEN Advanced Science Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan,
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  • Noriko Gotoh
    Affiliations
    the Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,
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  • Takanori Ishida
    Affiliations
    the Department of Surgical Oncology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8578, Japan,
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  • Satoshi Inoue
    Affiliations
    the Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan,

    the Departments of Anti-Aging Medicine and Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and
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  • Hiroaki Kitano
    Affiliations
    the Systems Biology Institute, 5-6-9 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
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  • Mariko Okada-Hatakeyama
    Correspondence
    To whom correspondence may be addressed: 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Tel.: 81-45-503-9302; Fax: 81-45-903-9613;
    Affiliations
    the Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan,
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  • Author Footnotes
    * This work was supported by Genome Network Project and Cell Innovation Program, Ministry of Education, Culture, Sports, Science and Technology, Japan and the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation, Japan.
    The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S4 and Figs. S1 and S2.
    1 Both authors contributed equally to this work.
Open AccessPublished:November 02, 2010DOI:https://doi.org/10.1074/jbc.M110.156877
      Quantitative phosphoproteome and transcriptome analysis of ligand-stimulated MCF-7 human breast cancer cells was performed to understand the mechanisms of tamoxifen resistance at a system level. Phosphoproteome data revealed that WT cells were more enriched with phospho-proteins than tamoxifen-resistant cells after stimulation with ligands. Surprisingly, decreased phosphorylation after ligand perturbation was more common than increased phosphorylation. In particular, 17β-estradiol induced down-regulation in WT cells at a very high rate. 17β-Estradiol and the ErbB ligand heregulin induced almost equal numbers of up-regulated phospho-proteins in WT cells. Pathway and motif activity analyses using transcriptome data additionally suggested that deregulated activation of GSK3β (glycogen-synthase kinase 3β) and MAPK1/3 signaling might be associated with altered activation of cAMP-responsive element-binding protein and AP-1 transcription factors in tamoxifen-resistant cells, and this hypothesis was validated by reporter assays. An examination of clinical samples revealed that inhibitory phosphorylation of GSK3β at serine 9 was significantly lower in tamoxifen-treated breast cancer patients that eventually had relapses, implying that activation of GSK3β may be associated with the tamoxifen-resistant phenotype. Thus, the combined phosphoproteome and transcriptome data set analyses revealed distinct signal transcription programs in tumor cells and provided a novel molecular target to understand tamoxifen resistance.

      Introduction

      Seventy percent of breast cancers are estrogen receptor (ER)-dependent
      The abbreviations used are: ER
      estrogen receptor
      TamR
      tamoxifen-resistant
      E2
      17β-estradiol
      HRG
      heregulin
      GSK
      glycogen-synthase kinase
      CREB
      cAMP-responsive element-binding protein
      IGF-IR
      insulin-like growth factor I receptor
      GO
      gene ontology.
      and initially respond to an estrogen antagonist-like tamoxifen. However, ∼30% of tamoxifen-responsive tumors eventually become resistant to this drug (
      • Musgrove E.A.
      • Sutherland R.L.
      ,
      • Riggins R.B.
      • Schrecengost R.S.
      • Guerrero M.S.
      • Bouton A.H.
      ). To understand development of tamoxifen resistance and define alternative therapy targets for tamoxifen-resistant tumors, numerous efforts have been made to determine responsible molecular and cellular mechanisms. Earlier studies suggested that, in addition to ER loss and abnormality of ER function (
      • Massarweh S.
      • Osborne C.K.
      • Creighton C.J.
      • Qin L.
      • Tsimelzon A.
      • Huang S.
      • Weiss H.
      • Rimawi M.
      • Schiff R.
      ), long term exposure to tamoxifen eventually increases signaling activities of ErbB receptors, insulin-like growth factor I receptor (IGF-IR), PI3K-Akt, and MAPK (
      • Campbell R.A.
      • Bhat-Nakshatri P.
      • Patel N.M.
      • Constantinidou D.
      • Ali S.
      • Nakshatri H.
      ,
      • Gee J.M.
      • Robertson J.F.
      • Ellis I.O.
      • Nicholson R.I.
      ,
      • Knowlden J.M.
      • Hutcheson I.R.
      • Jones H.E.
      • Madden T.
      • Gee J.M.
      • Harper M.E.
      • Barrow D.
      • Wakeling A.E.
      • Nicholson R.I.
      ). In addition, these elevated signaling activities cause unidentified transcriptional regulations in drug-resistant tumors that are different from sensitive ones (
      • Biswas D.K.
      • Singh S.
      • Shi Q.
      • Pardee A.B.
      • Iglehart J.D.
      ,
      • Lewis J.S.
      • Jordan V.C.
      ,
      • Nahta R.
      • Yu D.
      • Hung M.C.
      • Hortobagyi G.N.
      • Esteva F.J.
      ). However, although individual studies have identified respective key molecules and cellular mechanisms responsible for tamoxifen resistance, the entire landscape of signaling, gene regulation, and a linkage of these two biochemical events in tamoxifen-sensitive and insensitive tumors is totally unknown. In this study, we performed integrative phosphoproteome and transcriptome analysis of 17β-estradiol (E2) and heregulin (HRG)-stimulated WT and tamoxifen-resistant (TamR) MCF-7 human breast cancer cells to identify differences in their signaling-transcription regulatory program. In total, we experimentally identified 286 proteins and 1,603 genes for which phosphorylation or gene expression levels changed upon ligand stimulation. Analysis of the data sets for pathway and motif activity identified deregulated activation of GSK3β (glycogen-synthase kinase 3β) and MAPK signaling modules associated with altered activation of downstream CREB and AP-1 transcription factors in TamR cells. The current study provides the system-wide understanding of the signaling and transcriptional programs in tamoxifen-resistant tumor cells.

      DISCUSSION

      Overall, our phosphoproteome and transcriptome analyses revealed a distinct signaling and gene regulation signature in tamoxifen-resistant MCF-7 cells. Although our current analysis particularly highlighted deregulation of MAPK and GSK3β, proteins that potentially control gene expression through AP-1 and CREB transcription factors, our results indicated that tamoxifen resistance is achieved by quantitative changes in multiple signaling pathways.
      Earlier studies have indicated that elevated expression and activation of membrane receptor kinase signaling in tumors and cultured cells acquired tamoxifen resistance. In the current study, we could capture the elevated phosphorylation levels of ErbB3, PI3K, and MAPK in TamR cells in an unbiased fashion. Overexpression of membrane receptor kinases, such as EGF receptor, ErbB2, and IGF-IR, often correlates with a loss of ER and poor prognosis (
      • Stewart A.J.
      • Johnson M.D.
      • May F.E.
      • Westley B.R.
      ,
      • Schiff R.
      • Massarweh S.A.
      • Shou J.
      • Bharwani L.
      • Mohsin S.K.
      • Osborne C.K.
      ). Particularly, mRNA and protein expression of IGF-IR are known to be up-regulated in response to administration of E2 in MCF-7 cells. In this way, IGF-I and E2 act synergistically to promote progression of MCF-7 cells. Although our proteome analysis criteria failed to identify an increase of IGF-IR phosphorylation in response to E2, up-regulated phosphorylation of ErbB3 (after 1 h) (supplemental Fig. S2) and an elevated expression of EGF receptor mRNA (after 2–6 h) (Fig. 4B) were identified in the HRG-stimulated TamR cells. EGF receptor and ErbB3 form heterodimers to induce MAPK and PI3K activation (
      • Yarden Y.
      • Sliwkowski M.X.
      ); therefore induction of these genes might have an additive effect to enhance their kinase activities in TamR cells (supplemental Fig. S2).
      Regarding transcriptional regulation, it is known that AP-1 DNA binding activity and phosphorylation of c-JUN are up-regulated in the tamoxifen-resistant MCF-7 cells and human breast tumors (
      • Johnston S.R.
      • Lu B.
      • Scott G.K.
      • Kushner P.J.
      • Smith I.E.
      • Dowsett M.
      • Benz C.C.
      ). Furthermore, ER-dependent ERE transcription is suppressed by c-JUN (
      • Doucas V.
      • Spyrou G.
      • Yaniv M.
      ,
      • Shemshedini L.
      • Knauthe R.
      • Sassone-Corsi P.
      • Pornon A.
      • Gronemeyer H.
      ). Therefore, elevated AP-1 activity associated with c-JUN activation might target ER and alter its transcriptional capability in TamR cells.
      In this study, we did not take into account the functional roles of ER isoforms, ER-α and ER-β, which have distinct roles in normal breast tissues and tamoxifen-resistant breast cancer progression. ER-α is responsible for mediating E2-dependent gene expression of proteoglycans and extracellular metalloproteases that are associated with cellular transformation (
      • Kousidou O.Ch.
      • Berdiaki A.
      • Kletsas D.
      • Zafiropoulos A.
      • Theocharis A.D.
      • Tzanakakis G.N.
      • Karamanos N.K.
      ), and indeed, matrix metalloprotease 1 expression was up-regulated for 6 h after E2 administration in MCF-7 WT (Fig. 4B). Interestingly, although transcriptional activity of both ER-α and ER-β is modulated by estrogen and tamoxifen, the two ERs differently control E2-dependent AP-1 transcription. Particularly, ER-β is able to mediate an agonistic effect of anti-estrogens for AP-1 activation (
      • Tremblay G.B.
      • Tremblay A.
      • Copeland N.G.
      • Gilbert D.J.
      • Jenkins N.A.
      • Labrie F.
      • Giguère V.
      ,
      • Paech K.
      • Webb P.
      • Kuiper G.G.
      • Nilsson S.
      • Gustafsson J.
      • Kushner P.J.
      • Scanlan T.S.
      ). ER-β mRNA is significantly up-regulated in tamoxifen-resistant breast cancer patients (
      • Speirs V.
      • Malone C.
      • Walton D.S.
      • Kerin M.J.
      • Atkin S.L.
      ). However, the transcriptional activity of ER-β is negatively regulated by activation of the PI3K-Akt pathway (
      • Sanchez M.
      • Sauvé K.
      • Picard N.
      • Tremblay A.
      ), which is often highly activated in TamR cells (
      • Massarweh S.
      • Osborne C.K.
      • Creighton C.J.
      • Qin L.
      • Tsimelzon A.
      • Huang S.
      • Weiss H.
      • Rimawi M.
      • Schiff R.
      ,
      • Hynes N.E.
      • Lane H.A.
      ). Thus, regulation of each ER isoform is highly complex and diverse at different disease stages. Nevertheless, a functional balance between ER-α and ER-β seems to determine the overall output of ER activity. Thus, it is most likely that the phosphorylation responses to E2 and growth factor in WT and TamR cells observed in the current analysis are signatures of the status of these ER signaling responses. Particularly, our phosphoproteome data suggest that the E2 response is dramatically changed by acquisition of tamoxifen resistance.
      Ultimately, we could show that the activation/phosphorylation status of GSK3β is definitively associated with disease-free and breast cancer-specific survival of patients who received tamoxifen therapy. It might be argued that relapsed patients may not have responded to tamoxifen in the first place rather than having acquired resistance. Further analyses are needed to resolve this uncertainty. Also the global relationship between GSK3β status and ERK and other transcriptional activators should be elucidated in future work. In our current analysis, GSK3β was viewed as one of the most important hubs in the signal transcriptional network in tamoxifen-resistant breast cancer. Our study strongly suggested that cross-talk between ER and the membrane receptor signaling and interplays between signaling and gene expression medicate the ultimate effect on phenotypic outcomes of breast cancer.

      Acknowledgments

      We thank Yuko Saeki, Naomi Inagaki, Hiromi Wada, Keiko Takahashi, Miwako Tochigi, Kaori Ide, Kaoru Takahashi, and Michiko Murohashi for large scale preparation and molecular analysis of MCF-7 cells and transcriptional assay and Takashi Adachi for phosphoproteome data processing. We are also thankful to Dr. Seisuke Hattori, Dr. Naoyuki Iida, and Dr. Shinya Tasaki for providing advice on sample preparation using Phos-tag.

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