Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Anti-cancer agents in medicinal chemistry (Impact Factor: 2.47). 07/2009; 9(5):481-99. DOI: 10.2174/187152009788451833
Source: PubMed


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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    • "For these reasons, researchers are working on the development of SERMs without any of their harmful effects (Peng et al., 2009). But it is also true that there isn’t the appropriate data which compares the existing several SERMs’ potency for MCF-7 cells and TAM-R cells. "
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    ABSTRACT: Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to estrogen receptors (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. Unfortunately, the use of tamoxifen is associated with acquired resistance and some undesirable side effects. This study investigated the availability of the conventional SERMs on the TAM-resistance breast cancer cells. SERMs showed more effectiveness in MCF-7 cells than tamoxifen resistant cells, except toremifene and ospemifene. Especially, toremifene was more efficacious in tamoxifen resistant cells than MCF-7. Ospemifene had similar cytotoxic activity on the two types of breast cancers. The other SERMs used in this experiment didn't inhibit efficiently the proliferation of tamoxifen resistant cells. These results support the possibility to usage of toremifene on tamoxifen resistant cancer. The effectiveness by toremifene on tamoxifen resistant cells might be different pathways from the apoptosis and the autophagy. Further study should be needed to elucidate the underlying mechanism of effect of toremifene on tamoxifen resistant cancer.
    Toxicological Research 06/2011; 27(2):85-93. DOI:10.5487/TR.2011.27.2.085
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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. "
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    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 · 5.33 Impact Factor
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    • "Several anti-estrogenic synthetic compounds exist, such as tamoxifen and ICI 182,780 (fulvestrant), which prevent activation of the Akt and ERK pathways by virtue of their competition with E2 for binding to the ER [39]. Unfortunately, the use of these antiestrogens have undesirable side effects such as ICI 182,780 resulting in a complete blockade of activation pathways of ER and tamoxifen resulting in detrimental uterotrophic effects and can act as agonist for breast cancer cell growth [39], [40]. Overall, these damaging effects warrant the research for safer alternatives to synthetic antiestrogens. "
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    ABSTRACT: Thyroid cancer is the most common endocrine related cancer with increasing incidences during the past five years. Current treatments for thyroid cancer, such as surgery or radioactive iodine therapy, often require patients to be on lifelong thyroid hormone replacement therapy and given the significant recurrence rates of thyroid cancer, new preventive modalities are needed. The present study investigates the property of a natural dietary compound found in cruciferous vegetables, 3,3'-diindolylmethane (DIM), to target the metastatic phenotype of thyroid cancer cells through a functional estrogen receptor. Thyroid cancer cell lines were treated with estrogen and/or DIM and subjected to in vitro adhesion, migration and invasion assays to investigate the anti-metastatic and anti-estrogenic effects of DIM. We observed that DIM inhibits estrogen mediated increase in thyroid cell migration, adhesion and invasion, which is also supported by ER-α downregulation (siRNA) studies. Western blot and zymography analyses provided direct evidence for this DIM mediated inhibition of E(2) enhanced metastasis associated events by virtue of targeting essential proteolytic enzymes, namely MMP-2 and MMP-9. Our data reports for the first time that DIM displays anti-estrogenic like activity by inhibiting estradiol enhanced thyroid cancer cell proliferation and in vitro metastasis associated events, namely adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were determined to be targets of DIM. This anti-estrogen like property of DIM may lead to the development of a novel preventive and/or therapeutic dietary supplement for thyroid cancer patients by targeting progression of the disease.
    PLoS ONE 01/2011; 6(1):e15879. DOI:10.1371/journal.pone.0015879 · 3.23 Impact Factor
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