Effect of Vinca alkaloids on ERα levels and Estradiol-induced responses in MCF-7 cells

Abstract

Vinca alkaloids (VAs) such as Vincristine, Vinblastine and Vinorelbine are antineoplastic drugs that inhibit tubulin polymerisation into microtubules, induce mitotic G2/M arrest, activate c-Jun N-terminal kinase (JNK) and induce apoptosis. Although there are many studies evaluating the effect of VAs on breast cancer patients, until now little was known about how these compounds and estradiol signaling pathways might interfere. In this report, we show for the first time that VAs decreased ERalpha protein levels in the human breast cancer cell line MCF-7; VAs induced a parallel decrease in estrogen receptor mRNA. All the VAs tested inhibited estradiol (E2) mediated transactivation at ERE-driven promoters. E2 inhibited VAs-induced AP1 stimulation in MCF-7, but this inhibition was not observed when E2 is added 24 h in advance of VAs treatment. In contrast to the reported preventing effect over taxol-mediated apoptosis, E2 did not prevent VAs-induced cell death and interestingly, addition of E2 24 hours in advance of VAs treatment resulted in an increase of the number of cells undergoing apoptosis. Similar results were observed when E2 is replaced by other proliferation signals such as EGF. These results demonstrate that in the breast cancer cell-line MCF-7, E2-induced proliferation before VAs treatment enhances the apoptotical response to VAs which might have important implications in clinica.