Integrative genome-wide expression analysis bears evidence of estrogen receptor-independent transcription in heregulin-stimulated MCF-7 cells.
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.
Nagashima
Takeshi
T
Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Yokohama, Japan.
Suzuki
Takahiro
T
Kondo
Shinji
S
Kuroki
Yoko
Y
Takahashi
Kaoru
K
Ide
Kaori
K
Yumoto
Noriko
N
Hasegawa
Aki
A
Toyoda
Tetsuro
T
Kojima
Toshio
T
Konagaya
Akihiko
A
Suzuki
Harukazu
H
Hayashizaki
Yoshihide
Y
Sakaki
Yoshiyuki
Y
Hatakeyama
Mariko
M
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*
D020890:Neuregulin-1; D011960:Receptors, Estrogen; D012694:Serine