Integrative genome-wide expression analysis bears evidence of estrogen receptor-independent transcription in heregulin-stimulated MCF-7 cells

Takeshi Nagashima, Takahiro Suzuki, Shinji Kondo, Yoko Kuroki, Kaoru Takahashi, Kaori Ide, Noriko Yumoto, Aki Hasegawa, Tetsuro Toyoda, Toshio Kojima, Akihiko Konagaya, Harukazu Suzuki, Yoshihide Hayashizaki, Yoshiyuki Sakaki, Mariko Hatakeyama

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6 Citations (Scopus)

Abstract

Heregulin ß-1 (HRG) is an extracellular ligand that activates mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI3K)/AKt signaling pathways through ErbB receptors, MAPK and Akt have been shown to phosphorylatte the estrogen receptor (ER) at Ser-118 and Ser-167, respectively, thereby mimicking the effects of estrogenic activity such as estrogen responsive element (ERE)-dependent transcription. In the current study, integrative analysis was performed using two tiling array platforms, comprising histone H3 lysine 9 (H3K9) acetylation and RNA mapping, together with array comparative genomic hybridization (CGH) analysis in an effort to identify HRG-regulated genes in ER-positive MCF-7 breast cancer cells. Through application of various threshold setting, 333 (326 up-regulated and 7 down-regulated) HRG-regulated genes were detected. Prediction of upstream transcription factors (TFs) and pathway analysis indicated that 21% of HRG-induced gene regulation may be controlled by the MAPK cascade, while only 0.6% of the gene expression is controlled by ERE. A comparison with previously reported estrogen (E2)-regulated gene expression data revealed that only 12 common genes were identified between the 333 HRG-regulated (3.6%) and 239 E2-regulated (5.0%) gene groups. However, with respect to enriched upstream TFs, 4 common TFs were identified in the 14 HRG-regulated (28.6%) and 13 E2-regulated (30.8%) gene groups. These results indicated that while E2 and HRG may induce common TFs, the regulatory mechanisms that govern HRG- and E2-induced gene expression differ.

Original languageEnglish
Article numbere1803
JournalPloS one
Volume3
Issue number3
DOIs
Publication statusPublished - 2008 Mar 19

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Nagashima, T., Suzuki, T., Kondo, S., Kuroki, Y., Takahashi, K., Ide, K., Yumoto, N., Hasegawa, A., Toyoda, T., Kojima, T., Konagaya, A., Suzuki, H., Hayashizaki, Y., Sakaki, Y., & Hatakeyama, M. (2008). Integrative genome-wide expression analysis bears evidence of estrogen receptor-independent transcription in heregulin-stimulated MCF-7 cells. PloS one, 3(3), [e1803]. https://doi.org/10.1371/journal.pone.0001803