Figure 3.

The development of tamoxifen (TAM)-resistant breast cancer and the changing role of oestradiol (E₂) in the life and death of ER-positive cancer cells. (A) E₂-stimulated growth is inhibited by the use of an aromatase inhibitor to block oestrogen synthesis or TAM to block the ER and prevent oestrogen-stimulated gene transcription. Optimal antioestrogenic effects occur in the absence of pre-existing cell surface signalling mechanisms. (B) Prolonged use of TAM promotes an increase in HER2/neu cell surface signalling that creates a survival pathway phosphorylating the TAM ER complex and coactivator proteins. The transcription complex becomes activated to enhance gene activation and TAM-stimulated growth. If this is Phase I resistance, then oestrogen will also promote growth; so an aromatase inhibitor is an appropriate second-line therapy. If it is Phase II resistance, E₂ causes apoptosis. (C) In Phase II tamoxifen resistance, the E₂ ER complex collapses the survival mechanisms by dramatically reducing the level of cell surface signalling by preventing HER2/neu mRNA transcription and the nuclear level of NFκB, a transcription factor. (D) In Phase II tamoxifen resistance, the E₂ ER complex also enhances the synthesis of Fas receptor mRNA and protein which, in the presence of Fas ligand (FasL) activates caspase 8 and a cascade of events resulting in apoptosis. These figures are summaries of the mechanisms described in Osipo et al (2003) and Liu et al (2003).