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: 2.94). 07/2009; 9(5):481-99. DOI: 10.2174/187152009788451833
Source: PubMed

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.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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.
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.53 Impact Factor