Oestrogen treatment enhances the sensitivity of hormone-resistant breast cancer cells to doxorubicin

Abstract

Recently, it was shown that the resistance of breast cancer cells to growth-stimulating oestrogen action may be accompanied with the paradoxical tumour sensitization to oestrogen apoptotic action. In the present paper, we studied the influence of oestrogens on the sensitivity of resistant breast tumours to cytostatic drugs, and to evaluate the role of NF-κB (nuclear factor κB) signalling in the regulation of the apoptotic response of the resistant cells. The experiments were carried out on the oestrogen-dependent MCF-7 breast cancer cells and resistant MCF-7/LS subline generated through long-term cultivation of the parental cells in the absence of oestrogen. The cell treatment with the combination of oestradiol and Dox (doxorubicin) was found to enhance the apoptotic action of Dox in MCF-7/LS cells but not in the parent cells. MCF-7/LS cells were characterized by the increased level of ROS (reactive oxygen species) and decreased NF-κB activity. Oestradiol in combination with Dox leads to significant NF-κB stimulation and its accumulation in the nucleus of MCF-7/LS cells. The knockdown of NF-κB with siRNA (small interfering RNA) increased the apoptotic response of the MCF-7/LS cells to both Dox and oestradiol demonstrating the important role of NF-κB in the protection of the MCF-7/LS cells against apoptosis. In general, the results obtained show that: (i) oestradiol enhances the apoptotic action of Dox in the resistant breast cancer cells; and (ii) suppression of NF-κB signalling amplifies the apoptotic response of the resistant cells to both oestrogen and Dox, demonstrating that NF-κB may serve as a potential target in the therapy of the resistant breast cancer.