Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer

Masaaki Oyama, Takeshi Nagashima, Takashi Suzuki, Hiroko Kozuka-Hata, Noriko Yumoto, Yuichi Shiraishi, Kazuhiro Ikeda, Yoko Kuroki, Noriko Gotoh, Takanori Ishida, Satoshi Inoue, Hiroaki Kitano, Mariko Okada-Hatakeyama

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)818-829
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number1
DOIs
Publication statusPublished - 2011 Jan 7

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Oyama, M., Nagashima, T., Suzuki, T., Kozuka-Hata, H., Yumoto, N., Shiraishi, Y., Ikeda, K., Kuroki, Y., Gotoh, N., Ishida, T., Inoue, S., Kitano, H., & Okada-Hatakeyama, M. (2011). Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer. Journal of Biological Chemistry, 286(1), 818-829. https://doi.org/10.1074/jbc.M110.156877