Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

Oncogene. 2007 Oct 11;26(46):6619-29. doi: 10.1038/sj.onc.1210487. Epub 2007 May 7.


In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor (EGF) trigger association of the androgen receptor (AR)-estradiol receptor (ER) (alpha or beta) complex with Src. This interaction activates Src and affects the G1 to S cell cycle progression. In this report, we identify the sequence responsible for the AR/Src interaction and describe a 10 amino-acid peptide that inhibits this interaction. Treatment of the human prostate or mammary cancer cells (LNCaP or MCF-7, respectively) with nanomolar concentrations of this peptide inhibits the androgen- or estradiol-induced association between the AR or the ER and Src the Src/Erk pathway activation, cyclin D1 expression and DNA synthesis, without interfering in the receptor-dependent transcriptional activity. Similarly, the peptide prevents the S phase entry of LNCaP and MCF-7 cells treated with EGF as well as mouse embryo fibroblasts stimulated with androgen or EGF. Interestingly, the peptide does not inhibit the S phase entry and cytoskeletal changes induced by EGF or serum treatment of AR-negative prostate cancer cell lines. The peptide is the first example of a specific inhibitor of steroid receptor-dependent signal transducing activity. The importance of these results is highlighted by the finding that the peptide strongly inhibits the growth of LNCaP xenografts established in nude mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Androgen Receptor Antagonists
  • Animals
  • Breast Neoplasms / metabolism
  • Humans
  • Male
  • Mice
  • Peptides
  • Prostatic Neoplasms / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Receptors, Androgen / metabolism*
  • Receptors, Estradiol / antagonists & inhibitors
  • Receptors, Estradiol / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • src Homology Domains / physiology*


  • Androgen Receptor Antagonists
  • Peptides
  • Receptors, Androgen
  • Receptors, Estradiol
  • Proto-Oncogene Proteins pp60(c-src)