Enhancement of tamoxifen-induced E-cadherin function by Ca2+ channel antagonists in human breast cancer MCF7/6 cells

Abstract

Despite its intensive use in adjuvant breast cancer therapy for more than 30 years, the exact mechanisms of action of tamoxifen have not yet been fully characterized. Tamoxifen was recently shown to restore the Ecadherin function of human breast cancer MCF7/6 cells and to suppress their invasive phenotype. Because tamoxifen interacts with targets implicated in Ca 2+ homeostasis, we explored the possibility that the restoration of E-cadherin function in MCF7/6 cells induced by this drug could be affected by Ca 2+ modulators. Two different Ca 2+ channel antagonists (verapamil and nifedipine) potentiated the effect of tamoxifen on E-cadherin function, as evaluated with a fast cell aggregation assay. These molecules decreased the tamoxifen concentration needed to restore the E-cadherin function from 10 -6 M to 10 -7 M. When incubated with a Ca 2+ channel agonist, Bay K8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl)-pyridine-5-carboxylate), the effect of tamoxifen on E-cadherin function was completely abolished. These results demonstrate that the restoration of the E-cadherin function induced by tamoxifen depends, at least in part, on a Ca 2+ pathway, and support the evidence of an effect of tamoxifen on Ca 2+ -dependent mechanisms. Our data also suggest that Ca 2+ channel modulators could make it possible to decrease the dose of tamoxifen administered to patients without reducing the therapeutic effects.

Annexin I modulates cell functions by controlling intracellular calcium release

“…Removal of calcium abolishes adhesive activity of cadherins, renders cadherins vulnerable to proteases, and induces a dramatic reversible conformational change in their extracellular region (43,44). An association between reduced E-cadherin expression and enhanced tumor invasion and metastasis has been described (45)(46)(47)(48). The actual function of E-cadherin is mediated by a group of cytoplasmic proteins termed catenins, the loss or dysfunction of which has been implicated in the gain of tumor cell invasive potential (49,50).…”

Gynaecological effects of tamoxifen.

“…The drug may aVect intracellular signal transduction by acting directly on cell membranes. [58][59][60][61][62][63] It has oestrogen receptor independent eVects on apoptosis 64 65 and local growth control mechanisms. [66][67][68][69][70][71][72][73][74][75] In premenopausal women, it may disrupt the function of the hypothalamic-pituitaryovarian axis.…”

Η Επίδραση Της Ορμονικής Θεραπείας, Της Τιβολόνης Και Της Ραλοξιφαίνης Στην Έκφραση Της Επιθηλιακής Καντχερίνης Και Του Αγγειοενδοθηλιακού Αυξητικού Παράγοντα Σε Τραχηλικά Επιθηλιακά Κύτταρα Μετεμμηνοπαυσιακών Γυναικών

“…Ως εκτούτου, θα μπορούσαμε να συμπεράνουμε ότι, σε μοριακό επίπεδο, τα ευρήματά μας για τη δράση των σκευασμάτων οιστρογόνων-προγεσταγόνων είναι συνεπή ως προς τα στοιχεία των ΗERS και WHI. SERMs, βρέθηκε να αποκαθιστά τη λειτουργία του μορίου σε καρκινικά κύτταρα μαστού, εξαρτώμενη, τουλάχιστον μερικώς, από το ασβέστιο(Bracke et al 1994, Charlier et al 1996. Επιπλέον, σε ό,τι αφορά σε άλλα μέλη της οικογένειας των καντχερινών, η ραλοξιφαίνη φαίνεται να μειώνει τα επίπεδα της αγγειοενδοθηλιακής καντχερίνης (VE-cadherin) στον ορό, διατηρώντας, έτσι, την παρουσία της στα ενδοθηλιακά κύτταρα).…”