Author/Authors :
Rob Michalides، نويسنده , , Rob and Griekspoor، نويسنده , , Alexander and Balkenende، نويسنده , , Astrid and Verwoerd، نويسنده , , Desiree and Janssen، نويسنده , , Lennert and Jalink، نويسنده , , Kees and Floore، نويسنده , , Arno and Velds، نويسنده , , Arno and van `t Veer، نويسنده , , Laura and Neefjes، نويسنده , , Jacques، نويسنده ,
Abstract :
Using a novel approach that detects changes in the conformation of ERα, we studied the efficacy of anti-estrogens to inactivate ERα under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERα by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERα-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERα. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIα, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIα converts tamoxifen from an ERα inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).
