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

研究成果: Article査読

37 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)818-829
ページ数12
ジャーナルJournal of Biological Chemistry
286
1
DOI
出版ステータスPublished - 2011 1 7

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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