However, most tumours that initially respond to antihormones retain expression of the ER when they become refractory to such treatments , with loss of ER expression in tumours that have relapsed on tamoxifen being reported in less than one-quarter of cases [9-11].
For example, the acquisition of resistance to the antihormones tamoxifen and fulvestrant in ER-positive breast cancer cells is accompanied by the enhanced expression of the EGFR and HER2, as well as ligands for these receptors [12,18,28,29] whilst increased expression and activity of EGFR and HER2 and enhanced MAPK is reported in sequential samples obtained from tamoxifen-treated ER-positive primary breast cancers .
Combining antihormones with inhibitors of EGFR, HER2, MAPK and AKT signalling has been demonstrated to be significantly more effective in the suppression of cell growth compared with each as a single agent [20,31,64,65].
Despite the undoubted improvements in the treatment of breast cancer patients achieved with antihormones, resistance to such treatments, either acquired or de novo, remains a significant problem.
It is becoming apparent that the inappropriate activation of growth factor signalling pathways plays a prominent role in the promotion of antihormone failure in breast cancer cells where bi-directional cross-talk between oestrogen receptor and growth factor signalling pathways can sustain tumour growth in the presence of these agents.
It thus follows that for ER-positive tumours, antihormone therapies are employed in order to compromise ER signalling and suppress proliferation of such cancers.
Currently available antihormone treatment strategies for ER-positive breast cancer consist of: targeting the ER itself through the use of the hormone receptor antagonists such as the selective oestrogen receptor modulator (SERM) tamoxifen; or depriving the cancer cells of their oestrogenic stimulus through either gonadal suppression (in premenopausal women) or aromatase inhibitors (in the postmenopausal setting).
By binding to gonadal cells, these antagonistic antihormones
block activity by well-known forms of FSH, thereby disrupting normal hormone secretion.