Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer

Using a novel approach that detects changes in the conformation of ER(x, we studied the efficacy of anti-estrogens to inactivate ER(x under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERalpha by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERalpha-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERalpha. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-Rlalpha, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-Rlalpha converts tamoxifen from an ERa inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).