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Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
1Correspondence: Department of Pharmacology and Cancer Biology, Duke University Medical Center, 6259 LSRC, Box 3813, Durham, NC 27710, USA. E-mail: donald.mcdonnel{at}duke.edu
THE ESTROGEN RECEPTOR (ER) signal transduction pathway is the primary target of the hormonal therapies used for the treatment and prevention of breast cancer. Interestingly, although animal studies performed over a century ago first suggested a link between the ovaries (estrogen production) and growth of breast tumors, definition of the molecular basis for this association and its pharmaceutical exploitation has occurred relatively recently. In the realm of breast cancer chemotherapy, compounds like tamoxifen have emerged which function as antiestrogens by directly blocking the binding of estrogen(s) to their receptors in breast tumors. The aromatase inhibitors, such as letrazole and anastrazole, inhibit estrogen production while high dose progestins attenuate ER signaling by an as yet unknown mechanism. Together, these hormonal therapies have been extremely successful and have improved both mortality and morbidity in this disease. However, as we begin to fully understand the complexities of estrogen signaling, it is clear that new classes of drugs that regulate important components of this signaling pathway are going to emerge that will increase the armamentarium of the oncologist and improve overall prognosis in this disease.
Estrogen-containing medicines have been marketed in the United States for the relief of climacteric symptoms in postmenopausal women since 1942 and for contraception since 1960. However, at the time of approval, little was known about the mechanism(s) underlying the biological responses to these drugs in target tissues. In the late 1950s, Elwood Jensen and colleagues identified a high affinity intracellular binding protein (now known as ER
) that was found only in estrogen-responsive tissues (1)
. This was followed some years later by work from Bert O’Malley’s group which demonstrated that ER was in fact a ligand-dependent transcription factor, whose actions dictated the cellular response to estrogens (2)
. These discoveries, and those of other investigators, in the early years of molecular endocrinology enabled the development of a simple model to describe the actions of estrogens in target cells, the essence of which has stood the test of time. Specifically, these models proposed that in the absence of hormone, ER resided in cells in an inactive form that underwent a biochemical "activating" event upon binding an estrogen. The agonist-bound ER was then capable of interacting with specific DNA sequences within the regulatory regions of target genes and positively or negatively regulating their transcription. By extension, it was proposed that antiestrogens, much like competitive enzyme antagonists, functioned by binding to the hormone-binding pocket of ER, thus blocking agonist access. Interestingly, there were early indications that this elegant model and proposed mechanism of action was over simplified and did not explain the full complexity of ER pharmacology. Notably, Harper and Walpole observed in their early studies of the antiestrogen tamoxifen that whereas it functioned as a potent antagonist of estrogen action in some organs, it manifested robust agonist activity in others (3)
. These observations were not followed up on to any great extent until the studies of Love et al. in 1992 revealed that tamoxifen, in the context of adjuvant chemotherapy for breast cancer, exhibited a paradoxical agonist activity in bone (4)
. Indeed, so dramatic were the results in these bone studies that it led to the rebirth of ER as a drug discovery target, this time for drugs useful for the treatment and prevention of osteoporosis. Expectedly, the heightened interest in ER modulators for osteoporosis and the accompanying advancement in our understanding of estrogen action have also had a positive impact on the development of ER modulators for breast cancer.
One of the most significant advances in drug discovery efforts aimed at identifying new ER modulators is the dramatic move in recent years from empirical to predictive mechanism-based drug screens. Traditionally, discovery programs for ER modulators used receptor-binding assays as a primary screen with the subsequent use of a "predictive" secondary assay to evaluate the relative activity of selected compounds in relevant endpoints. Compounds with desired properties were then assayed in animal models of the targeted disease for efficacy. Most, if not all, of the currently approved ER modulators emerged from programs that used this general methodology. For the identification of compoundswith pure agonist or antagonist activity, this approach has generally been successful. However, the observation that tamoxifen could function as a tissue-selective estrogen/antiestrogen set the field off in a challenging new direction where the goal was to identify Selective Estrogen Receptor Modulators (SERMs), ER ligands that manifest estrogenic activities in bone, in the cardiovascular system, and in the CNS, but which are neutral, or function as antagonists, in the breast and the uterus. Tamoxifen is by this definition a SERM, although it is not an ideal drug as it manifests uterotrophic activity, a risk factor for endometrial cancer. Furthermore, it is only one-third as efficacious as estrogen in bone. Raloxifene, a second generation SERM, is somewhat improved in that it spares the uterus but, like tamoxifen, it only functions as a partial ER agonist in bone. There is no expectation that the newer SERMs currently in clinical trials will have any major advantage, other than potency, over existing compounds. This realization, coupled with a very high degree of attrition of SERMs in late phase clinical trials, indicates that progress in this area will likely require a return to "first principles" and the subsequent implementation of mechanism-based approaches for discovery to complement established empirical approaches.
As recently as ten years ago, the idea of mechanism-based ER modulator screens could not have been contemplated. However, there have been tremendous advances of late in our understanding of the molecular determinants of ER pharmacology, which in totality have provided the tools needed to implement mechanism-based approaches for ER modulator discovery. Although a complete description of the field as it stands is beyond the scope of this perspective, it is worth mentioning the most important of these advances. One of the biggest surprises was the discovery, in 1996, of a second estrogen receptor, ERß, to complement that discovered by Jensen (ER) (5)
. In some cells, the primary function of this receptor subtype is to modulate the activities of estradiol-activated ER. In addition, however, ERß appears to be involved directly in the regulation of signaling pathways unrelated to reproductive function, such as inflammation. This has raised interest in developing ER subtype-selective agonists. The second major advance was the observation that the overall shape of ER and ß is plastic and substantially impacted by the nature of the bound ligand (6)
. The relevance of this observation was highlighted by the demonstration that receptor conformation is the primary regulator of the ability of ER to interact with transcriptional coactivators and corepressors, the proteins responsible for manifesting the transcriptional effect of the DNA-bound receptor (7)
. Finally, it has been determined that ER can interact with at least 50 functionally distinct coactivators and corepressors, the relative and absolute levels of which can differ greatly between different cells. With respect to the development of breast cancer preventatives, these advances are being used to develop compounds that can block the association of ER with the coactivators required for estrogen-driven proliferation and metastasis of breast cancer cells while preserving, or even enhancing, the interaction of the receptor with factors involved in bone homeostasis. With respect to the development of breast cancer treatments, it should be appreciated that agents that facilitate robust corepressor recruitment to target gene promoters are likely to have useful therapeutic properties.
Interestingly, a new class of drugs has emerged called Selective Estrogen Receptor Degraders (SERDs) that induce a conformational change in ER and target it for proteasomal degradation. Definition of the receptor interacting proteins responsible for this activity should enable the development of compounds with improved efficacy or selectivity, possibly targeting only ER in breast. Regardless of the clinical application, it is clear that the next generation of ER modulators will come from mechanism-based screens that capitalize on our understanding of the a) "cofactor interactome" of the receptor and b) structural basis for differential recruitment by the receptor of these cofactors to target gene promoters. What is needed at the current time is a more complete understanding of the expression level and roles of each of the relevant ER cofactors in target cells/tissues of interest. Armed with this information, it will be possible to screen for compounds that facilitate the recruitment of one particular cofactor at the expense of others, and in this manner, exquisite functional selectivity can be developed.
The NIH-sponsored ATLAS initiative has contributed significantly to these efforts by funding a comprehensive cataloguing of nuclear receptor/cofactor expression in a wide variety of tissues in both animal-derived and human tissues (8)
. Exploiting this knowledge should provide a wealth of new compounds with unique mechanism(s) of action that can be used for the treatment and prevention of breast cancer and for the treatment of other estrogenopathies.
FOOTNOTES
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals@faseb.org.
REFERENCES
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