Sex-steroid hormones and EGF signalling in breast and prostate cancer cells: targeting the association of Src with steroid receptors

Abstract

Sex-steroid hormones trigger association of their receptors with signalling effectors. Remarkably, various hormonal effects, such as DNA synthesis of different cell types are evoked by this association. In mammary and prostate cancer cells, EGF, androgen or estradiol trigger the assembly of AR/ER/Src complex. SH2-Src interacts with a phosphotyrosine residue of ER and SH3-Src interacts with a proline rich sequence of AR. This association stimulates Src-dependent signalling, DNA synthesis and cytoskeleton changes. We now report that in prostate or breast cancer cells stimulated by EGF or androgen or estradiol, small peptides (6-10 amino acids) derived from ER or AR sequences involved in the receptor interaction with Src, prevent AR/ER/Src association, Src/Erk pathway stimulation, cyclin D1 expression and DNA synthesis. The peptide action is restricted to cells expressing the steroid receptors and to signals mediated by these receptors. Remarkably, the peptides do not modify the steroid receptor-dependent transcriptional activity. Growth of prostate or mammary cancer cell xenografts is strongly inhibited by these novel receptor antagonists.