In spite of the considerable progress made, several important questions regarding ER-directed endocrine therapies remained unanswered. First, one must wonder why all breast cancers are not equally responsive to ER disruption. The malignant phenotype of a substantial portion (up to 50%) of breast cancers appears to be hormone (estrogen)-independent; therefore, classic ER-directed endocrine therapy provides little or no benefit to such patients.
Moreover, many patients whose tumors are initially hormone-dependent ultimately develop disease that is resistant to one or another of the endocrine strategies.
Surprisingly, these symptoms of breast cancer may remain sensitive to alternative hormone treatments for some period of time, but unfortunately most of these women ultimately develop completely hormone-independent disease and are destined to succumb to their malignancy.
Considerable insight into the mechanisms of cancer stages resistance has been provided by the remarkable advances in knowledge concerning the molecular biology of endocrine-responsive cancers. It is now well established that steroid hormones, such as estradiol, exert their effect by freely diffusing through the plasma membrane and binding to cytoplasmic peptide receptors. Binding of the steroid ligand with the receptor (in this case, estrogen and ER) induces ER homodimerization and phosphorylation, followed by interaction with estrogen response elements or ERE in the promoter regions of estrogen-dependent genes.
Recent work has demonstrated that at least two such ERs exist, ERa and ERb. Specific genetic function is dictated by carefully orchestrated interaction between the ER/ERE and intranuclear coactivating and corepressing proteins.
The precise cellular/tissue responses to estrogen or to other ligands such as the SERMs depends on the specific ligand, the balance of ERa and ERb, and the relative concentrations of multiple coactivators and repressors. Perhaps the best example of this exquisite balance is the apparent difference in tissue specificity between tamoxifen and raloxifene, a more recently introduced SERM. Both have antiestrogenic qualities in breast tissue and in the central nervous system, as well as both appear to be estrogenic in bone and liver. However, while the estrogenic effects of tamoxifen in the uterus accounts for part if not all of its associated increase in endometrial cancer, raloxifene appears to be an ER antagonist in the endometrium.
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