Insulin-like growth factor 1 differentially regulates estrogen receptor-dependent transcription at estrogen response element and AP-1 sites in breast cancer cells.
Cross-talk between insulin-like growth factor 1 (IGF-1) and estrogen receptor alpha (ER) regulates gene expression in breast cancer cells, but the underlying mechanisms remain unclear. Here, we studied how 17-beta-estradiol (E2) and IGF-1 affect ER transcriptional machinery in MCF-7 cells. E2 treatment stimulated ER loading on the estrogen response element (ERE) in the pS2 promoter and on the AP-1 motif in the cyclin D1 promoter. On ERE, similar amounts of liganded ER were found at 1-24-h time points, whereas on AP-1, ER binding fluctuated over time. At 1 h, liganded ER was recruited to ERE together with histone acetyltransferases SRC-1 and p300, ubiquitin ligase E6-AP, histone methyltransferase Carm1 (Carm), and polymerase (pol) II. This coincided with increased histone H3 acetylation and up-regulation of pS2 mRNA levels. At the same time, E2 moderately increased cyclin D1 expression, which was associated with the recruitment of liganded ER, SRC-1, p300, ubiquitin ligase E6-AP (E6L), Mdm2, and pol II, but not other regulatory proteins, to AP-1. In contrast, at 1 h, IGF-1 increased the recruitment of the ER.SRC-1.p300.E6L.Mdm2.Carm.pol II complex on AP-1, but not on ERE, and induced cyclin D1, but not pS2, mRNA expression. Notably, ER knockdown reduced the association of ER, E6L, Mdm2, Carm, and pol II with AP-1 and resulted in down-regulation of cyclin D1 expression. IGF-1 potentiated the effects of E2 on ERE but not to AP-1 and increased E2-dependent pS2, but not cyclin D1, mRNA expression. In conclusion, E2 and IGF-1 differentially regulate ER transcription at ERE and AP-1 sites.
Cascio
Sandra
S
Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia Pennsylvania 19122, USA.
Bartella
Viviana
V
Garofalo
Cecilia
C
Russo
Antonio
A
Giordano
Antonio
A
Surmacz
Eva
E
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008024:Ligands; D012333:RNA, Messenger / Q000096:biosynthesis*; D020218:Response Elements / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D047628:Estrogen Receptor alpha; D008024:Ligands; D012333:RNA, Messenger; C051838:TFF1 protein, human; D018808:Transcription Factor AP-1; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D004958:Estradiol; D007334:Insulin-Like Growth Factor I