Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation

Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestr adiol receptor beta with Src, activates the Src/Raf-1/Erk-2 pathway and sti mulates cell proliferation. Surprisingly, either androgen or oestradiol act ion on each of these steps is inhibited by both anti-androgens and anti-oes trogens. Similar findings for oestradiol receptor alpha were observed in MC F-7 or T47D cells stimulated by either oestradiol or androgens. Microinject ion of LNCaP, MCF-7 and T47D cells with SrcK(-) abolishes steroid-stimulate d S-phase entry. Data-from transfected Cos cells confirm and extend the fin dings from these cells. Hormone-stimulated Src interaction with the androge n receptor and oestradiol receptor alpha or beta is detected using glutathi one S-transferase fusion constructs. Src SH2 interacts with phosphotyrosine 537 of oestradiol receptor alpha and the Src SH3 domain with a proline-ric h stretch of the androgen receptor. The role of this phosphotyrosine is str essed by its requirement for association of oestradiol receptor alpha with Src and consequent activation of Src in intact Cos cells.