Mechanisms of tamoxifen resistance

Though the antiestrogen tamoxifen prolongs disease-free and overall survival in the adjuvant setting, and induces remissions in over half of the patients with estrogen receptor positive metastatic disease, all patients eventually acquire tamoxifen resistance. Furthermore, many of the resistant tumors actually appear to be stimulated by tamoxifen just as they are by estrogens. In both animal models and clinical specimens, we have found lower tamoxifen uptake and somewhat altered tamoxifen metabolism in resistant tumors, but neither appears to explain tamoxifen stimulation of the resistant tumors. Nor do estrogen receptor losses or mutations appear to explain this phenomenon, although altered expression of transcriptional variant forms of the receptor may well contribute. Pure steroidal antiestrogens such as ICI 182,780 are capable of reversing tamoxifen-stimulated as well as estrogen-stimulated growth of these resistant tumors, and are now in clinical trials for this purpose.