Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer
ABSTRACT Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors (ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.
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- "factsheets/populations/factsheet.asp?uno¼900). With the exemption of aromatase inhibitors that cause a complete deprivation of endogenous ligand by inhibiting the transformation of testosterone into 17b-estradiol, the majority of endocrine disruptors used in daily practice target estrogen receptors per se either by acting as pure antagonists or as mixed agonist/antagonists , depending on their structure, the cell type, and the recruited co-regulators (see Jordan, 2002; and Peng et al., 2009, for reviews). However, despite the significant progress in breast cancer treatment, as well as in women's survival and quality of life, the emergence of resistance to endocrine therapy remains a major problem of public health. "
ABSTRACT: In recent years, our knowledge on estrogen receptors (ER) has been modified profoundly with the identification and the deciphering of the role of its protein effectors, as well as with the deeper insight of its molecular structure/function dynamics, characteristics associated with its nucleo-cytoplasmic-membrane shuttling properties. Also, significant progress has been made concerning its turn-over and associated final proteasomal degradation processes. These advances could lead in the near future to the design and the synthesis of novel receptor-interacting drugs. Recently, a number of receptor-related peptides acting as specific ER ligands have been identified and extensively studied with respect to their estrogenic/antiestrogenic activities. Among them, ERα17p, a synthetic analog of the P(295)-T(311) sequence of ERα, has been shown to exert pseudo-estrogenic effects by interacting in the close vicinity of its hinge region (BF3 domain). Remarkably, this sequence appears as the epicenter of a number of post-transcriptional modifications as well as of the recruitment of co-regulators, suggesting that it would play a key role in ERα functions. Here, we provide evidence that ERα17p induces apoptosis in ERα-positive (MCF-7, T47D) and -negative (MDA-MB-231, SK-BR-3) breast cancer cells by an ERα-independent membrane mechanism, triggering major pro-apoptotic signaling cascades. Finally, ERα17p induces the regression of breast ERα-negative cancer tumor xenografts, without apparent toxicity, suggesting that it could represent a new attractive tool for the development of future promising therapeutic approaches, and providing a novel insight to ER regulation of cell fate.Molecular oncology 02/2011; 5(1):36-47. DOI:10.1016/j.molonc.2010.11.001 · 5.94 Impact Factor
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ABSTRACT: The purpose of the CoE is to discover the mechanism(s) of estrogen-induced apoptosis in advanced antihormone-resistant breast cancers using our unique models, and to establish the clinical value of short-term low-dose estrogen to reverse antihormone resistance in patients exhaustively treated with antihormone therapy. The clinical trial has begun enrolling patients, but enrollment has been low. We have addressed this by amending patient eligibility and expanding trial site locations. We have completed gene expression microarray hybridizations covering extended E2-treatment time courses of wild-type MCF-7:WS8, and of estrogen deprivation-resistant MCF-7:5C and MCF-7:2A cells, which undergo E2-induced apoptosis. Multiple custom methods have been developed for analyses of time-course microarray data. We have also conducted proteomic analyses, and identified proteins which differentially co-immunoprecipitate with the co-activator AIB1 or phospho-tyrosine complexes in an E2-dependent manner. Using the gene expression microarray and proteomic data, networks were built that highlight differential growth versus apoptosis pathways regulated by E2. Further, based on the microarray analyses, we investigated the G protein coupled-receptor GPR30, and the endoplasmic reticulum stress-associated factors caspase-4 and XBP1 in E2-induced growth or apoptosis. Finally, we surprisingly found that long-term treatment of MCF-7:5C cells with the c-Src inhibitor PP2 reversed E2-induced apoptosis.
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ABSTRACT: The progesterone receptor (PR) is estrogen regulated, and PR levels in breast tumors can be used to predict the success of endocrine therapies targeting the estrogen receptor (ER). Tanaproget is a nonsteroidal progestin agonist with very high PR binding affinity and excellent in vivo potency. When appropriately radiolabeled, it might be used to image PR-positive breast tumors noninvasively by positron emission tomography (PET). We describe the synthesis and PR binding affinities of a series of fluoroalkyl-substituted 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones, analogues of Tanaproget. Some of these compounds have subnanomolar binding affinities, higher than that of either Tanaproget itself or the high affinity PR ligand R5020. Structure-binding affinity relationships can be rationalized by molecular modeling of ligand complexes with PR, and the enantioselectivity of binding has been predicted. These compounds are being further evaluated as potential diagnostic PET imaging agents for breast cancer, and enantiomerically pure materials of defined stereochemistry are being prepared.Journal of Medicinal Chemistry 03/2010; 53(8):3349-60. DOI:10.1021/jm100052k · 5.48 Impact Factor