title: Integrative genome-wide expression analysis bears evidence of estrogen receptor-independent transcription in heregulin-stimulated MCF-7 cells.
abstract: Heregulin beta-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 phosphorylate 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 settings, 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.
authors: Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Yokohama, Japan.
authors: Takeshi
authors: T
authors: Nagashima
authors: Takahiro
authors: T
authors: Suzuki
authors: Shinji
authors: S
authors: Kondo
authors: Yoko
authors: Y
authors: Kuroki
authors: Kaoru
authors: K
authors: Takahashi
authors: Kaori
authors: K
authors: Ide
authors: Noriko
authors: N
authors: Yumoto
authors: Aki
authors: A
authors: Hasegawa
authors: Tetsuro
authors: T
authors: Toyoda
authors: Toshio
authors: T
authors: Kojima
authors: Akihiko
authors: A
authors: Konagaya
authors: Harukazu
authors: H
authors: Suzuki
authors: Yoshihide
authors: Y
authors: Hayashizaki
authors: Yoshiyuki
authors: Y
authors: Sakaki
authors: Mariko
authors: M
authors: Hatakeyama
mesh_terms: D045744:Cell Line, Tumor; D015894:Genome, Human; D006801:Humans; D020890:Neuregulin-1 / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D020890:Neuregulin-1; D011960:Receptors, Estrogen; D012694:Serine