Promoting E2F1-mediated apoptosis in oestrogen receptor-alpha-negative breast cancer cells (BMC Cancer)

Background: Because oestrogen receptor alpha (ERalpha) regulates E2F1 expression to mediate tamoxifen resistance in ERalpha-positive breast cancer cells, we aimed to define the possible roles of ERalpha and E2F1 in promoting the resistance of ERalpha-negative breast cancer cells to 4-hydroxy-tamoxifen (4OHT). Methods: This study utilised conventional techniques to demonstrate the effects of 4OHT on the expression of ERalpha and E2F1 and also examined the individual and combined effects of 4OHT with dipyridamole (DIPY) and 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin (TMCG) on the oestrogen-negative MDA-MB-231 breast cancer cell line using viability assays, Hoechst staining, MALDI-TOF mass spectroscopy, and confocal microscopy. Results: Despite the ERalpha-negative status of the MDA-MB-231 cells, we observed that 4OHT efficiently up-regulated ERalpha in these cells and that this upregulation promoted E2F1-mediated cell growth. Because E2F1 plays a dual role in cell growth/apoptosis, we designed a therapy incorporating TMCG/DIPY to take advantage of the elevated E2F1 expression in these 4OHT-treated cells. 4OHT enhances the toxicity of TMCG/DIPY in these ERalpha-negative breast cancer cells. Conclusions: Because TMCG/DIPY treatment modulates the methylation status/stability of E2F1, the results demonstrate that therapies targeting the epigenetic machinery of cancer cells in the presence of overexpressed E2F1 may result in efficient E2F1-mediated cell death.