ENHANCEMENT OF TAMOXIFEN-INDUCED E-CADHERIN FUNCTION BY CA2-CANCER MCF7( CHANNEL ANTAGONISTS IN HUMAN BREAST)6 CELLS/

Despite its intensive use in adjuvant breast cancer therapy for more t han 30 years, the exact mechanisms of action of tamoxifen have not yet been fully characterized. Tamoxifen was recently shown to restore the E-cadherin function of human breast cancer MCF7/6 cells and to suppre ss their invasive phenotype. Because tamoxifen interacts with targets implicated in Ca2+ homeostasis, we explored the possibility that the r estoration of E-cadherin function in MCF7/6 cells induced by this drug could be affected by Ca2+ modulators. Two different Ca2+ channel anta gonists (verapamil and nifedipine) potentiated the effect of tamoxifen on E-cadherin function, as evaluated with a fast cell aggregation ass ay. These molecules decreased the tamoxifen concentration needed to re store the E-cadherin function from 10(-6) M to 10(-7) M. When incubate d with a Ca2+ channel agonist, Bay K8644 (2-trifluoromethylphenyl)-pyr idine-5-carboxylate), the effect of tamoxifen on E-cadherin function w as completely abolished. These results demonstrate that the restoratio n of the E-cadherin function induced by tamoxifen depends, at least in part, on a Ca2+ pathway, and support the evidence of an effect of tam oxifen on Ca2+-dependent mechanisms. Our data also suggest that Ca2+ c hannel modulators could make it possible to decrease the dose of tamox ifen administered to patients without reducing the therapeutic effects .