Cellular and molecular pharmacology of antiestrogen action and resistance.

Antiestrogen therapy remains one of the most widely used and effective treatments for the management of endocrine responsive breast cancers. This reflects the ability of antiestrogens to compete with estrogens for binding to estrogen receptors. Whereas response rates of up to 70% are reported in patients with tumors expressing estrogen and progesterone receptors, most responsive tumors will eventually acquire resistance. The most important factor in de novo resistance is lack of expression of these receptors. However, the mechanisms driving resistance in tumors that express estrogen and/or progesterone receptors are unclear. A tamoxifen-stimulated phenotype has been described, but seems to occur only in a minority of patients. Most tumors (>80%) may become resistant through other, less well defined, resistance mechanisms. These may be multifactorial, including changes in immunity, host endocrinology, and drug pharmacokinetics. Significant changes within the tumor cells may also occur, including alterations in the ratio of the estrogen receptor alpha:beta forms and/or other changes in estrogen receptor-driven transcription complex function. These may lead to perturbations in the gene network signaling downstream of estrogen receptors. Cells may also alter paracrine and autocrine growth factor interactions, potentially producing a ligand-independent activation of estrogen receptors by mitogen-activated protein kinases. Antiestrogens can affect the function of intracellular proteins and signaling that may, or may not, involve estrogen receptor-mediated events. These include changes in oxidative stress responses, specific protein kinase C isoform activation, calmodulin function, and cell membrane structure/function.