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. 2004 Jun;5(6):597-605.
doi: 10.1016/j.ccr.2004.05.016.

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

Rob Michalides  1 , Alexander Griekspoor, Astrid Balkenende, Desiree Verwoerd, Lennert Janssen, Kees Jalink, Arno Floore, Arno Velds, Laura van't Veer, Jacques Neefjes
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Free article

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

Rob Michalides et al. Cancer Cell. 2004 Jun.
Free article

Abstract

Using a novel approach that detects changes in the conformation of ERalpha, we studied the efficacy of anti-estrogens to inactivate ERalpha 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-RIalpha, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIalpha converts tamoxifen from an ERalpha inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).

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