Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway

Cancer Res. 2006 Nov 15;66(22):11039-46. doi: 10.1158/0008-5472.CAN-06-2442.


Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes. SRC-3 is frequently amplified and/or overexpressed in hormone-sensitive and hormone-insensitive tumors. We reported previously that SRC-3 stimulated prostate cell growth in a hormone-independent manner through activation of AKT signaling pathway. However, the underlying mechanism remains undefined. Here, we exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis. We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival. In contrast, knockdown of SRC-3 in PC3 (androgen receptor negative) prostate cancer cells and MCF-7 breast cancer cells reduces their expression. Similarly, in prostate glands of SRC-3 null mice, expressions of these components in the IGF/AKT signal pathway are also reduced. Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3. Interestingly, we showed that recruitment of SRC-3 to two target promoters, IRS-2 and IGF-I, requires transcription factor activator protein-1 (AP-1). Taken together, our results clearly show that SRC-3 and AP-1 can coordinately regulate the transcription of multiple components in the IGF/AKT pathway to ensure ligand-independent cell proliferation and survival of cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Histone Acetyltransferases / biosynthesis
  • Histone Acetyltransferases / deficiency
  • Histone Acetyltransferases / genetics*
  • Humans
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Coactivator 3
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Proto-Oncogene Proteins c-akt / genetics*
  • Signal Transduction
  • Somatomedins / biosynthesis
  • Somatomedins / genetics*
  • Trans-Activators / biosynthesis
  • Trans-Activators / deficiency
  • Trans-Activators / genetics*
  • Transcription Factor AP-1 / biosynthesis
  • Transcription Factor AP-1 / genetics*
  • Transcription, Genetic
  • Transfection
  • Up-Regulation


  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Phosphoproteins
  • Somatomedins
  • Trans-Activators
  • Transcription Factor AP-1
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3
  • Proto-Oncogene Proteins c-akt