Treatment with the pure antiestrogen faslodex (ICI 182780) induces tumor necrosis factor receptor 1 (TNFR1) expression in MCF-7 breast cancer cells

Apoptosis induction by the pure antiestrogen faslodex, also known as ICI 18 2780 (ICI), is associated with an effective down-regulation of Bcl-2 expres sion in the human breast cancer cell line MCF-7. Recent observations point out that beside members of the Bcl-2 family also the TNFR1 signaling pathwa y may be involved in apoptosis induction by antiestrogens. In this report w e have analyzed the expression of members of the TNFR1 signaling pathway du ring the apoptotic process induced by the pure antiestrogen faslodex and by tamoxifen (Tam) in MCF-7 breast cancer cells. Treatment with 10(-7) M ICI or 10(-7) M Tam leads to a time dependent increase of TNFR1 and TRADD stead y-state mRNA levels in MCF-7 cells. In contrast, Bcl-2 expression was stron gly decreased following administration of ICI but only weakly after adminis tration of Tam. Western blot analysis and studies by the use of fluorescenc e microscopy and flow cytometry revealed a time dependent induction of TNFR 1 protein and cell surface expression in MCF-7 cells in response to treatme nt with ICI. To investigate if TNFR1 is functionally involved in apoptosis induction by antiestrogens, we tested whether TNFR1 blocking antibodies can counteract the growth inhibitory action of Tam and ICI. Coincubation of MC F-7 cells with antiestrogens (ICI or Tam) and blocking TNFR1 antibodies lea d to an increase in cell viability. Our results provide evidence for a cros s talk between the TNFR1 signaling pathway and antiestrogens during the pro cess of apoptosis induction in MCF-7 breast cancer cells. The superiority o f the pure antiestrogen ICI to induce apoptosis in MCF-7 cells may result f rom its capability to modulate the induction of apoptosis via Bcl-2 as well as TNF-associated signal transduction pathways.