Hormonal Resistance and Metastasis: ER-coregulator-Src Targeted Therapy
Annual rept. 1 Sep 2008-31 Aug 2009
TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO
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The estrogen receptor ER, is implicated in the progression of breast cancer. Endocrine therapy is shown to have a positive effect on the treatment of breast cancer. Despite the positive effects, initial or acquired resistance to endocrine therapies frequently occurs. Accumulating evidence suggests that ER-coregulators play an essential role in hormonal responsiveness and cancer progression to metastasis. In this study, we have generated model cells that have defects in coregulator PELP1-Src signaling axis. Using these models, we demonstrated that ER-nongenotropic actions play an important role in cell motilityinvasion. Our data suggest that PELP1 and Src kinase play an essential role in the activation of ER nongenomic signaling leading to cytoskeleton reorganization and migration. Pharmacological inhibition of Src kinase using dasatinib significantly inhibited E2-mediated nongenomic actions. These results suggest that the ER-Src-PELP1 axis is a novel target for preventing the emergence of metastatic cells and that dasatinib may have therapeutic utility in blocking ER-positive metastases.
- Medicine and Medical Research