The role of agonistic metabolites in tamoxifen resistance of breast cancer

• Applicants: Dr. Thomas E. Mürdter; Dr. Werner Schroth
• Subject Area: Pharmacology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244756013

The selective estrogen receptor (ER) modulator tamoxifen is used for the treatment of all stages of breast cancer to block estrogen dependent cell proliferation. About 30% of treated patients relapse, which is attributed to adaptive changes of the tumor but also to the metabolism of tamoxifen and its variability. Tamoxifen requires activation into the anti estrogenic metabolites endoxifen und 4-hydroxytamoxifen by liver cytochrome P450 (CYP)-enzymes, particularly CYP2D6. The current hypothesis of a CYP2D6 dependent formation of antiestrogenic metabolites and positive or negative effect on tamoxifen outcome showed limitations with respect to outcome prediction. This may be explained by the highly complex tamoxifen metabolism, which among the more than 20 known metabolites yields antiestrogenic but also mitogenic estrogenic metabolites. The goal of the current proposal is to determine pharmacokinetic, pharmacodynamic and pharmacogenetic characteristics of estrogen-like tamoxifen metabolites and to investigate their potential contribution to tamoxifen resistance. This includes the characterization of the metabolic pathways involved in their formation and inactivation as well as their effects on ER signal transduction. Moreover, we will investigate the influence of enzyme genetic variants and non-genetic factors on their formation and elimination in vitro and perform in vivo association studies. The latter will rely on the investigation of 450 available tamoxifen treated patients (600 aromatase inhibitor-treated patients for comparison) of an ongoing observational clinical trial to establish predictive biomarkers for tamoxifen outcome.

• DFG Programme: Research Grants