1,720,960 research outputs found
Strategies to degrade estrogen receptor α in primary and ESR1 mutant-expressing metastatic breast cancer.
No full textWith the advent of omic technologies, our understanding of the molecular mechanisms underlying estrogen receptor α (ERα)-expressing breast cancer (BC) progression has grown exponentially. Nevertheless, the most widely used therapy for inhibiting this disease is endocrine therapy (ET) (i.e., aromatase inhibitors, tamoxifen - Tam, faslodex/fulvestrant - FUL). However, in a considerable number of cases, prolonged patient treatment with ET generates the development of resistant tumor cells and, consequently, tumor relapse, which manifests as metastatic disease that is extremely difficult to manage, especially because such metastatic BCs (MBCs) often express ERα mutations (e.g., Y537S, D538G) that confer pronounced growth advantages to tumor cells. Interestingly, ET continues to be the therapy of choice for this neoplasia, which underscores the need to identify novel drugs that could work in primary and MBCs. In this study, we review the approaches that have been undertaken to discover these new anti-ERα compounds, especially considering those focused on evaluating ERα degradation. A literature analysis demonstrated that current strategies for discovering new anti-BC drugs are focusing on the identification either of novel ERα inhibitors, of compounds that inhibit ERα-related pathways or of drugs that influence ERα-unrelated cellular pathways. Several lines of evidence suggest that all of these molecules alter the ERα content and block the proliferation of both primary and MBCs. In turn, we propose to rationalize all these discoveries into the definition of e.m.eral.d.s (i.e., selective modulators of ERα levels and degradation) as a novel supercategory of anti-ERα drugs that function both as modulators of ERα levels and inhibitors of BC cell proliferation
Real-time measurement of E2: ERα transcriptional activity in living cells.
No full textKinetic analyses of diverse physiological processes have the potential to unveil new aspects of the molecular regulation of cell biology at temporal levels. 17β-estradiol (E2) regulates diverse physiological effects by binding to the estrogen receptor α (ERα), which primarily works as a transcription factor. Although many molecular details of the modulation of ERα transcriptional activity have been discovered including the impact of receptor plasma membrane localization and its relative E2-evoked signaling, the knowledge of real-time ERα transcriptional dynamics in living cells is lacking. Here, we report the generation of MCF-7 and HeLa cells stably expressing a modified luciferase under the control of an E2-sensitive promoter, which activity can be continuously monitored in living cells and show that E2 induces a linear increase in ERα transcriptional activity. Ligand-independent (e.g., epidermal growth factor) receptor activation was also detected in a time-dependent manner. Kinetic profiles of ERα transcriptional activity measured in the presence of both receptor antagonists and inhibitors of ERα plasma membrane localization reveal a biphasic dynamic of receptor behavior underlying novel aspects of receptor-regulated transcriptional effects. Finally, analysis of the rate of the dose-dependent E2 induction of ERα transcriptional activity demonstrates that low doses of E2 induce an effect identical to that determined by high concentrations of E2 as a function of the duration of hormone administration. Overall, we present the characterization of sensitive stable cell lines were to study the kinetic of E2 transcriptional signaling and to identify new aspects of ERα function in different physiological or pathophysiological conditions
In silico screening for ERα down modulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells.
No full textPURPOSE: Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (ICI 182,780; ICI). Unfortunately, a high fraction of ET treated women relapses and becomes resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using modulation of the intracellular ERα content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells. METHODS: We screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells. RESULTS: We found that mitoxantrone and thioridazine induced ERα downmodulation and prevented MCF-7 BC cell proliferation. Interestingly, while mitoxantrone was found to be toxic for normal breast epithelial cells, thioridazine showed a preferential activity towards BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα expressing BC cells. CONCLUSIONS: We suggest that modulation of the intracellular ERα concentration in BC cells can be exploited in in silico screens to identify anti-BC drugs and uncover a re-purposing opportunity for thioridazine in the treatment of primary and metastatic ET resistant BCs
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds Against ERalpha Expressing Breast Cancer Cells
Get PDFAbstract: 17-estradiol (E2) exerts its physiological effects through the estrogen receptor (i.e.,
ER). The E2:ER signaling allows the regulation of cell proliferation. Indeed, E2 sustains the
progression of ER positive (ER+) breast cancers (BCs). The presence of ER at the BC diagnosis
drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression.
Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available.
Consequently, the actual challenge is to complement the drugs available to fight ER+ primary
and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and
Drug Administration (FDA)-approved drugs inhibiting E2:ER signaling to cell proliferation in
cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo)
and fenticonazole (Fenti) induce ER degradation and prevent ER transcriptional signaling and
proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and
Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the
CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “antiestrogens”-
like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a
valuable method to rapidly identify bioactive compounds with anti-estrogenic activity
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