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Sample records for estrogen receptor-positive human

  1. Differential expression of the MT-1E gene in estrogen-receptor-positive and -negative human breast cancer cell lines.

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    Friedline, J A; Garrett, S H; Somji, S; Todd, J H; Sens, D A

    1998-01-01

    The goal of this study was to determine which of the 10 functional metallothionein (MT) genes are expressed in four human breast cancer cell lines and whether expression varies among the cell lines. Using reverse transcription polymerase chain reaction (RT-PCR) technology, it was shown that there was no expression of mRNA for the MT-1A, MT-1B, MT-1F, MT-1G, MT-1H, MT-3, and MT-4 genes in any of the four cell lines. All four cell lines were shown to express mRNA for the MT-2A and MT-1X genes. The expression level of mRNA for the MT-2A gene demonstrated modest differences among the cell lines, whereas expression of the MT-1X gene was consistent. In contrast, mRNA for the MT-1E gene was expressed in only two of the four cell lines and expression correlated to the estrogen receptor status of the cell lines. The two estrogen-receptor-positive cell lines showed no mRNA expression for the MT-1E gene. In the two estrogen-receptor-negative cell lines, mRNA expression for the MT-1E gene was elevated with expression levels similar to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. The cellular content of MT protein was also shown to be elevated in the estrogen-receptor-negative cell lines that express MT-1E mRNA. These results suggest a possible relationship between estrogen receptor status and MT-1E gene expression in human breast cancer.

  2. Establishment of a normal-derived estrogen receptor-positive cell line comparable to the prevailing human breast cancer subtype

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    Hopkinson, Branden Michael; Klitgaard, Marie Christine; Petersen, Ole William

    2017-01-01

    Understanding human cancer increasingly relies on insight gained from subtype specific comparisons between malignant and non-malignant cells. The most frequent subtype in breast cancer is the luminal. By far the most frequently used model for luminal breast cancer is the iconic estrogen receptor......-positive (ERpos) MCF7 cell line. However, luminal specific comparisons have suffered from the lack of a relevant non-malignant counterpart. Our previous work has shown that transforming growth factor-β receptor (TGFβR) inhibition suffices to propagate prospectively isolated ERpos human breast luminal cells from...... reduction mammoplasties (HBEC). Here we demonstrate that transduction of these cells with hTERT/shp16 renders them immortal while remaining true to the luminal lineage including expression of functional ER (iHBECERpos). Under identical culture conditions a major difference between MCF7 and normal...

  3. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

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    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Hong, Darong [Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Jung, Bom; Park, Min-Ju [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Kim, Jong-Ho, E-mail: jonghokim@khu.ac.kr [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

    2015-08-07

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

  4. Xenoestrogens modulate genotoxic (UVB)-induced cellular responses in estrogen receptors positive human breast cancer cells.

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    Cargouët, Maëlle; Bimbot, Maya; Levi, Yves; Perdiz, Daniel

    2006-07-01

    Human populations and wildlife are exposed to mixtures of both anthropogenic and natural chemicals. Some of these compounds are known to interact principally with the endocrine function, whereas others act mainly on genomic DNA. Given this evidence, we wanted to address the question of whether concomitant exposure of such chemicals was able to interact at the cellular level. We have previously shown that 17β-Estradiol (E(2)) modulates the DNA repair capacity of cells. In this work, we wanted to examine if other xenoestrogens (i.e. industrial compounds, pesticides or pharmaceuticals) were able to interact with the UVB-induced cellular response as E(2) does. Here, we show that xenoestrogens modulate the capacity of cells to repair their DNA damage according to the type of compounds. For example, the oral contraceptive 17α-Ethinylestradiol down-regulated the repair of UVB-induced DNA damage whereas the UV filter Eusolex 6007 up-regulated this pathway. The notion that xenoestrogens could interact with a genotoxic stress is reinforced by the modulation of the estrogens-dependent luciferase reporter gene expression when cells are UVB-irradiated. Finally, these observations suggested the potential role of xenoestrogens in carcinogenesis by their capacity to modulate cells responses to genotoxic stress.

  5. Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7

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    Gaube, Friedemann; Wolfl, Stefan; Pusch, Larissa; Kroll, Torsten C; Hamburger, Matthias

    2007-01-01

    Background Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic black cohosh rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7. Results Both extract and purified compounds clearly inhibited cellular proliferation. Gene expression profiling with the extract allowed us to identify 431 regulated genes with high significance. The extract induced expression pattern differed from those of 17β-estradiol or the estrogen receptor antagonist tamoxifen. We observed a significant enrichment of genes in an anti-proliferative and apoptosis-sensitizing manner, as well as an increase of mRNAs coding for gene products involved in several stress response pathways. These functional groups were highly overrepresented among all regulated genes. Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1. In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated. Real-Time RT-PCR analysis of 13 selected genes was conducted after treatment with purified compounds – the cycloartane-type triterpene glycoside actein and triterpene aglycons – showing similar expression levels compared to the extract. Conclusion No estrogenic but antiproliferative and proapoptotic gene expression was shown for black cohosh in MCF-7 cells at the transcriptional level. The effects may be results of the activation of different pathways. The cycloartane glycosides and – for the first time – their aglycons could be identified as an active principle in black cohosh. PMID:17880733

  6. Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.

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    Royce, Melanie; Bachelot, Thomas; Villanueva, Cristian; Özgüroglu, Mustafa; Azevedo, Sergio J; Cruz, Felipe Melo; Debled, Marc; Hegg, Roberto; Toyama, Tatsuya; Falkson, Carla; Jeong, Joon; Srimuninnimit, Vichien; Gradishar, William J; Arce, Christina; Ridolfi, Antonia; Lin, Chinjune; Cardoso, Fatima

    2018-03-22

    Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4

  7. Profiling of gene expression regulated by 17β-estradiol and tamoxifen in estrogen receptor-positive and estrogen receptor-negative human breast cancer cell lines

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    Rangel N

    2017-09-01

    Full Text Available Nelson Rangel,1,2 Victoria E Villegas,2 Milena Rondón-Lagos3 1Department of Medical Sciences, University of Turin, Turin, Italy; 2Faculty of Natural Sciences and Mathematics, Universidad del Rosario, Bogotá, Colombia; 3School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia Abstract: One area of great importance in breast cancer (BC research is the study of gene expression regulated by both estrogenic and antiestrogenic agents. Although many studies have been performed in this area, most of them have only addressed the effects of 17β-estradiol (E2 and tamoxifen (TAM on MCF7 cells. This study aimed to determine the effect of low doses of E2 and TAM on the expression levels of 84 key genes, which are commonly involved in breast carcinogenesis, in four BC cell lines differentially expressing estrogen receptor (ER α and HER2 (MCF7, T47D, BT474, and SKBR3. The results allowed us to determine the expression patterns modulated by E2 and TAM in ERα+ and ERα− cell lines, as well as to identify differences in expression patterns. Although the MCF7 cell line is the most frequently used model to determine gene expression profiles in response to E2 and TAM, the changes in gene expression patterns identified in ERα+ and ERα− cell lines could reflect distinctive properties of these cells. Our results could provide important markers to be validated in BC patient samples, and subsequently used for predicting the outcome in ERα+ and ERα− tumors after TAM or hormonal therapy. Considering that BC is a molecularly heterogeneous disease, it is important to understand how well, and which cell lines, best model that diversity. Keywords: breast cancer, cell lines, 17β-estradiol, tamoxifen, ERα+, ERα−, qPCR

  8. Mouse models of estrogen receptor-positive breast cancer

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    Shakur Mohibi

    2011-01-01

    Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

  9. Androgen receptor in estrogen receptor positive breast cancer: Beyond expression.

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    Basile, Debora; Cinausero, Marika; Iacono, Donatella; Pelizzari, Giacomo; Bonotto, Marta; Vitale, Maria Grazia; Gerratana, Lorenzo; Puglisi, Fabio

    2017-12-01

    In recent years, new therapeutic approaches have reshaped the overall strategy of breast cancer (BC) treatment and have markedly improved patient survival. This is, in part, due to novel therapies for estrogen receptor (ER)-positive BC. Unfortunately, many patients present de novo resistance to these therapies or develop an acquired resistance over time. Therefore, research is now focused on discovering new molecular targets to overcome these resistances. Interestingly, preclinical and clinical studies have shown a critical role for the cross-talk between androgen receptor (AR) and ER in luminal-like BC. AR is expressed in >60% of BC and in up to 90% of ERα-positive tumors. Multiple studies suggest that AR is associated with a favorable prognosis. However, AR overexpression and, in particular, the high AR:ER ratio, seem to be involved in resistance to hormonal treatment. In this setting, a group of BCs could benefit from AR-inhibitors; nevertheless, some ER-positive BC patients do not seem to benefit from this strategy. Therefore, it is crucial to identify biomarkers that would enable the selection of patients who might benefit from combination treatment with ER and AR inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Lineage-Biased Stem Cells Maintain Estrogen-Receptor-Positive and -Negative Mouse Mammary Luminal Lineages

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    Chunhui Wang

    2017-03-01

    Full Text Available Delineating the mammary differentiation hierarchy is important for the study of mammary gland development and tumorigenesis. Mammary luminal cells are considered a major origin of human breast cancers. However, how estrogen-receptor-positive (ER+ and ER− luminal cells are developed and maintained remains poorly understood. The prevailing model suggests that a common stem/progenitor cell generates both cell types. Through genetic lineage tracing in mice, we find that SOX9-expressing cells specifically contribute to the development and maintenance of ER− luminal cells and, to a lesser degree, basal cells. In parallel, PROM1-expressing cells give rise only to ER+ luminal cells. Both SOX9+ and PROM1+ cells specifically sustain their respective lineages even after pregnancy-caused tissue remodeling or serial transplantation, demonstrating characteristic properties of long-term repopulating stem cells. Thus, our data reveal that mouse mammary ER+ and ER− luminal cells are two independent lineages that are maintained by distinct stem cells, providing a revised mammary epithelial cell hierarchy.

  11. Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients.

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    Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Kuroda, Keiji; Matsuoka, Joe; Igari, Fumie; Himuro, Takanori; Yoshida, Yuko; Tokuda, Emi; Shimizu, Hideo; Hino, Okio; Saito, Mitsue

    2015-10-01

    Ki67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity. The Ki67 expression level, which indicates that a cell is undergoing division (cell cycle), rises when proliferation activity increases. Thus, Ki67 expression might be affected by hormonal stimuli. We hypothesised that Ki67 expression level might change during the menstrual cycle. We examined pairs of biopsy and surgical specimens from individual patients to evaluate this hypothesis. First, the effects of estradiol on Ki67 expression in breast cancer cell lines were examined employing immunocytochemistry and Western blotting. Next, differences in Ki67 expression between biopsy and surgical specimens from 131 patients with estrogen receptor-positive tumours were retrospectively examined. In vitro experiments showed Ki67 expression in estrogen receptor-positive cancer cells to be dependent on estradiol stimulation. Ki67 expression was higher in biopsy samples collected in the luteal phase than in those from other phases. When biopsy and surgical samples were obtained at different times during the menstrual cycle in the same individual, there were differences in Ki67 expression between these samples. Those collected in the luteal phase showed higher Ki67 expression than samples obtained during other phases (pKi67 expression varied in the same patients according to menstrual cycle phase. Our results suggest that Ki67 expression in estrogen receptor-positive breast cancer should be carefully assessed bearing in mind the patient's menstrual cycle, since the interpretation of expression could affect treatment decisions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Placental Kisspeptins Differentially Modulate Vital Parameters of Estrogen Receptor-Positive and -Negative Breast Cancer Cells

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    Rasoulzadeh, Zahra; Ghods, Roya; Kazemi, Tohid; Mirzadegan, Ebrahim; Ghaffari-Tabrizi-Wizsy, Nassim; Rezania, Simin; Kazemnejad, Somaieh; Arefi, Soheila; Ghasemi, Jamileh; Vafaei, Sedigheh; Mahmoudi, Ahmad-Reza; Zarnani, Amir-Hassan

    2016-01-01

    Kisspeptins (KPs) are major regulators of trophoblast and cancer invasion. Thus far, limited and conflicting data are available on KP-mediated modulation of breast cancer (BC) metastasis; mostly based on synthetic KP-10, the most active fragment of KP. Here, we report for the first time comprehensive functional effects of term placental KPs on proliferation, adhesion, Matrigel invasion, motility, MMP activity and pro-inflammatory cytokine production in MDA-MB-231 (estrogen receptor-negative) and MCF-7 (estrogen receptor-positive). KPs were expressed at high level by term placental syncytiotrophoblasts and released in soluble form. Placental explant conditioned medium containing KPs (CM) significantly reduced proliferation of both cell types compared to CM without (w/o) KP (CM-w/o KP) in a dose- and time-dependent manner. In MDA-MB-231 cells, placental KPs significantly reduced adhesive properties, while increased MMP9 and MMP2 activity and stimulated invasion. Increased invasiveness of MDA-MB-231 cells after CM treatment was inhibited by KP receptor antagonist, P-234. CM significantly reduced motility of MCF-7 cells at all time points (2–30 hr), while it stimulated motility of MDA-MB-231 cells. These effects were reversed by P-234. Co-treatment with selective ER modulators, Tamoxifen and Raloxifene, inhibited the effect of CM on motility of MCF-7 cells. The level of IL-6 in supernatant of MCF-7 cells treated with CM was higher compared to those treated with CM-w/o KP. Both cell types produced more IL-8 after treatment with CM compared to those treated with CM-w/o KP. Taken together, our observations suggest that placental KPs differentially modulate vital parameters of estrogen receptor-positive and -negative BC cells possibly through modulation of pro-inflammatory cytokine production. PMID:27101408

  13. Association of tissue inhibitor of metalloproteinases-1 and Ki67 in estrogen receptor positive breast cancer

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    Bjerre, Christina Annette; Knoop, Ann; Bjerre, Karsten

    2013-01-01

    The role of tissue inhibitor of metalloproteinases-1 (TIMP-1) in estrogen receptor (ER) positive breast cancer remains to be fully elucidated. We evaluated TIMP-1 as a prognostic marker in patients treated with adjuvant tamoxifen and investigated TIMP-1s association with Ki67 and ER/progesterone ....../progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) profiles....

  14. Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.

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    Shen, Tiansheng; Brandwein-Gensler, Margaret; Hameed, Omar; Siegal, Gene P; Wei, Shi

    2015-11-01

    Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P < .0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P = .0002) or ER-/PR+ (P = .0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P = .001) and disease-specific survival (P = .005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Low expression of a few genes indicates good prognosis in estrogen receptor positive breast cancer

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    Buechler Steven

    2009-07-01

    Full Text Available Abstract Background Many breast cancer patients remain free of distant metastasis even without adjuvant chemotherapy. While standard histopathological tests fail to identify these good prognosis patients with adequate precision, analyses of gene expression patterns in primary tumors have resulted in more successful diagnostic tests. These tests use continuous measurements of the mRNA concentrations of numerous genes to determine a risk of metastasis in lymph node negative breast cancer patients with other clinical traits. Methods A survival model is constructed from genes that are both connected with relapse and have expression patterns that define distinct subtypes, suggestive of different cellular states. This in silico study uses publicly available microarray databases generated with Affymetrix GeneChip technology. The genes in our model, as represented by array probes, have distinctive distributions in a patient cohort, consisting of a large normal component of low expression values; and a long right tail of high expression values. The cutoff between low and high expression of a probe is determined from the distribution using the theory of mixture models. The good prognosis group in our model consists of the samples in the low expression component of multiple genes. Results Here, we define a novel test for risk of metastasis in estrogen receptor positive (ER+ breast cancer patients, using four probes that determine distinct subtypes. The good prognosis group in this test, denoted AP4-, consists of the samples with low expression of each of the four probes. Two probes target MKI67, antigen identified by monoclonal antibody Ki-67, one targets CDC6, cell division cycle 6 homolog (S. cerevisiae, and a fourth targets SPAG5, sperm associated antigen 5. The long-term metastasis-free survival probability for samples in AP4- is sufficiently high to render chemotherapy of questionable benefit. Conclusion A breast cancer subtype defined by low

  16. Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy

    International Nuclear Information System (INIS)

    Takada, Mamoru; Miyazaki, Masaru; Sato-Otsubo, Aiko; Ogawa, Seishi; Kaneko, Yasuhiko; Higuchi, Toru; Tozuka, Katsunori; Takei, Hiroyuki; Haruta, Masayuki; Watanabe, Junko; Kasai, Fumio; Inoue, Kenichi; Kurosumi, Masafumi

    2013-01-01

    Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. We

  17. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

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    Keya De Mukhopadhyay

    Full Text Available In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

  18. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

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    Stacey, S.N.; Manolescu, A.; Sulem, P.; Thorlacius, S.; Gudjonsson, S.A.; Jonsson, G.F.; Jakobsdottir, M.; Bergthorsson, J.T.; Gudmundsson, J.; Aben, K.K.H.; Strobbe, L.J.; Swinkels, D.W.; Engelenburg, K.C.A. van; Henderson, B.E.; Kolonel, L.N.; Marchand, L. le; Millastre, E.; Andres, R.; Saez, B.; Lambea, J.; Godino, J.; Polo, E.; Tres, A.; Picelli, S.; Rantala, J.; Margolin, S.; Jonsson, T.; Sigurdsson, H.; Jonsdottir, T.; Hrafnkelsson, J.; Johannsson, J.; Sveinsson, T.; Myrdal, G.; Grimsson, H.N.; Sveinsdottir, S.G.; Alexiusdottir, K.; Saemundsdottir, J.; Sigurdsson, A.; Kostic, J.; Gudmundsson, L.; Kristjansson, K.; Masson, G.; Fackenthal, J.D.; Adebamowo, C.; Ogundiran, T.; Olopade, O.I.; Haiman, C.A.; Lindblom, A.; Mayordomo, J.I.; Kiemeney, L.A.L.M.; Gulcher, J.R.; Rafnar, T.; Thorsteinsdottir, U.; Johannsson, O.T.; Kong, A.; Stefansson, K.

    2008-01-01

    We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR

  19. Ki67 Heterogeneity in Estrogen Receptor-Positive Breast Cancers: Which Tumor Type Has the Most Heterogeneity?

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    Himuro, Takanori; Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Saito, Mitsue

    2016-04-01

    Heterogeneity of Ki67 expression, often seen in breast cancer, can make evaluation of the expression of this marker difficult and give rise to confusion when considering adjuvant treatments for patients. Herein, we investigated estrogen receptor-positive breast cancers to reveal the tumor characteristics associated with Ki67 heterogeneity. Surgical specimens from 85 invasive ductal carcinomas of no special type and 13 invasive lobular carcinomas were examined. We first calculated the differences between Ki67 expression in a hot spot and those in 4 random fields on the same slide. We then evaluated Ki67 heterogeneity within the tumor, based on these differences. Among clinicopathological factors, solid-tubular carcinoma, an architectural growth pattern subtype of invasive ductal carcinoma, correlated with high Ki67 heterogeneity (P Ki67 expression. © The Author(s) 2015.

  20. Estrogen receptor positive breast cancers and their association with environmental factors

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    Mannel Sylvio

    2011-05-01

    Full Text Available Abstract Background Epidemiological studies to assess risk factors for breast cancer often do not differentiate between different types of breast cancers. We applied a general linear model to determine whether data from the Surveillance, Epidemiology, and End Results Program on annual county level age-adjusted incidence rates of breast cancer with and without estrogen receptors (ER+ and ER- were associated with environmental pollutants. Results Our final model explained approximately 38% of the variation in the rate of ER+ breast cancer. In contrast, we were only able to explain 14% of the variation in the rate of ER- breast cancer with the same set of environmental variables. Only ER+ breast cancers were positively associated with the EPA's estimated risk of cancer based on toxic air emissions and the proportion of agricultural land in a county. Meteorological variables, including short wave radiation, temperature, precipitation, and water vapor pressure, were also significantly associated with the rate of ER+ breast cancer, after controlling for age, race, premature mortality from heart disease, and unemployment rate. Conclusions Our findings were consistent with what we expected, given the fact that many of the commonly used pesticides and air pollutants included in the EPA cancer risk score are classified as endocrine disruptors and ER+ breast cancers respond more strongly to estrogen than ER- breast cancers. The findings of this study suggest that ER+ and ER- breast cancers have different risk factors, which should be taken into consideration in future studies that seek to understand environmental risk factors for breast cancer.

  1. Divergent estrogen receptor-positive and -negative breast cancer trends and etiologic heterogeneity in Denmark

    DEFF Research Database (Denmark)

    Anderson, William F; Rosenberg, Philip S; Petito, Lucia

    2013-01-01

    Long-term breast cancer trends in incidence in the United States (US) show rising estrogen receptor (ER)-positive rates and falling ER-negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries...... with similar risk factor profiles. Therefore, we analyzed invasive female breast cancers in Denmark, a country with similar risk factors as the US. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic (1993-2010) and used age....... If current trends continue, ER-positive cancers will increase at least 13% by 2018 in Denmark, ER-negative cancers will fall 15% by 2018, and breast cancer overall will increase at least 7% by 2018. Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors...

  2. The β-glucan fromLentinus edodessuppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers.

    Science.gov (United States)

    Xu, Hui; Zou, Siwei; Xu, Xiaojuan

    2017-10-17

    Breast cancer is now the most common cancer in worldwide women, and novel interventions are needed to overcome the resistance occurring in the estrogen-targeted endocrine therapy. Herein, we demonstrate that the β-glucan from Lentinus edodes (LNT) exhibited a profound inhibition ratio of ∼53% against estrogen receptor positive (ER+) MCF-7 tumor growth in nude mice similar to the positive control of cisplatin. Immunohistochemistry images showed that LNT evidently suppressed cell proliferation and promoted apoptosis in MCF-7 tumor tissues. The Western blotting analysis indicated that LNT up-regulated the tumor suppressor p53, phosphorylated extracellular signal-regulated kinase1/2 (p-ERK1/2), cleaved-Caspase 3 and poly [ADP (ribose)] polymerase 1 (PARP 1) protein levels, and reduced the expression of mouse double minute 2 (MDM2), telomerase reverse transcriptase (TERT), nuclear factor-kappa B (NF-κB) p65, B-cell lymphoma-2 (Bcl-2), estrogen receptor α (ERα), etc. in tumor tissues. Moreover, LNT significantly suppressed phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt) and mammalian target of rapamycin (mTOR) protein levels. It was thus proposed that LNT inhibited MCF-7 tumor growth through suppressing cell proliferation and enhancing apoptosis possibly via multiple pathways such as PI3K/Akt/mTOR, NF-κB-, ERK-, ERα-, caspase- and p53-dependent pathways. Interestingly, the cell viability assay, siRNA transfection, Western blotting and flow cytometric analysis suggested that LNT targeted p53/ERα to only suppress cell proliferation via cell cycle arrest at G2/M phase without apoptosis in vitro . The big difference between in vivo and in vitro data suggested that the immune responses triggered by the polysaccharide should mainly contribute to the apoptotic effect in vivo . Overall, this work provides a novel strategy to treat ER+ breast cancers by using a naturally occurring β-glucan from mushrooms.

  3. Paralemmin-1 is over-expressed in estrogen-receptor positive breast cancers

    Directory of Open Access Journals (Sweden)

    Turk Casey M

    2012-05-01

    Full Text Available Abstract Background Paralemmin-1 is a phosphoprotein lipid-anchored to the cytoplasmic face of membranes where it functions in membrane dynamics, maintenance of cell shape, and process formation. Expression of paralemmin-1 and its major splice variant (Δ exon 8 as well as the extent of posttranslational modifications are tissue- and development-specific. Paralemmin-1 expression in normal breast and breast cancer tissue has not been described previously. Results Paralemmin-1 mRNA and protein expression was evaluated in ten breast cell lines, 26 primary tumors, and 10 reduction mammoplasty (RM tissues using real time RT-PCR. Paralemmin-1 splice variants were assessed in tumor and RM tissues using a series of primers and RT-PCR. Paralemmin-1 protein expression was examined in cell lines using Western Blots and in 31 ductal carcinomas in situ, 65 infiltrating ductal carcinomas, and 40 RM tissues using immunohistochemistry. Paralemmin-1 mRNA levels were higher in breast cancers than in RM tissue and estrogen receptor (ER-positive tumors had higher transcript levels than ER-negative tumors. The Δ exon 8 splice variant was detected more frequently in tumor than in RM tissues. Protein expression was consistent with mRNA results showing higher paralemmin-1 expression in ER-positive tumors. Conclusions The differential expression of paralemmin-1 in a subset of breast cancers suggests the existence of variation in membrane dynamics that may be exploited to improve diagnosis or provide a therapeutic target.

  4. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Chung, J H; Pavlick, D; Hartmaier, R; Schrock, A B; Young, L; Forcier, B; Ye, P; Levin, M K; Goldberg, M; Burris, H; Gay, L M; Hoffman, A D; Stephens, P J; Frampton, G M; Lipson, D M; Nguyen, D M; Ganesan, S; Park, B H; Vahdat, L T; Leyland-Jones, B; Mughal, T I; Pusztai, L; O'Shaughnessy, J; Miller, V A; Ross, J S; Ali, S M

    2017-11-01

    Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative. Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer. At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%). GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for

  5. Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Francescopaolo Di Cello

    Full Text Available Downregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of claudin 1 via DNA promoter methylation may thus be an important determinant in breast cancer development and progression. To investigate if silencing of claudin 1 has an epigenetic etiology in breast cancer we compared gene expression and methylation data from 217 breast cancer samples and 40 matched normal samples available through the Cancer Genome Atlas (TCGA. Moreover, we analyzed claudin 1 expression and methylation in 26 breast cancer cell lines. We found that methylation of the claudin 1 promoter CpG island is relatively frequent in estrogen receptor positive (ER+ breast cancer and is associated with low claudin 1 expression. In contrast, the claudin 1 promoter was not methylated in most of the ER-breast cancers samples and some of these tumors overexpress claudin 1. In addition, we observed that the demethylating agents, azacitidine and decitabine can upregulate claudin 1 expression in breast cancer cell lines that have a methylated claudin 1 promoter. Taken together, our results indicate that DNA promoter methylation is causally associated with downregulation of claudin 1 in a subgroup of breast cancer that includes mostly ER+ tumors, and suggest that epigenetic therapy to restore claudin 1 expression might represent a viable therapeutic strategy in this subtype of breast cancer.

  6. Estrogen Receptor- and Progesterone Receptor-Positive Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Yuichi Kinoshita

    2013-04-01

    Full Text Available The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC is a relatively rare tumor. We herein report the case of young woman with DSV-PTC who developed cervical lymph node recurrence 7 years after the initial surgery. A 15-year-old female patient with no medical or family history of thyroid tumors developed a thyroid neoplasm in the right lobe. Right thyroidectomy and regional lymphadenectomy were performed, and the tumor was diagnosed as DSV-PTC. She was followed up as an outpatient. Seven years after the surgery, cervical lymph node recurrence developed. On microscopic examination, the thyroid tumor showed a papillary growth pattern with numerous psammoma bodies and distinct fibrosis. Immunohistochemically, the tumor cells were estrogen receptor and progesterone receptor positive with reduced membranous expression of E-cadherin and were intermingled with S-100-positive dendritic/Langerhans cells. DSV-PTC is characterized by a strong tendency for invasion and metastasis. Thus, accurate diagnosis is clinically important, and a morphological and immunohistochemical understanding of DSV-PTC is necessary.

  7. The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor positive early stage breast cancer

    International Nuclear Information System (INIS)

    Fowble, B.; Fein, D.A.; Hanlon, A.L.; Eisenberg, B.L.; Hoffman, J.P.; Sigurdson, E.R.; Daly, M.B.; Goldstein, L.J.

    1995-01-01

    Purpose: In the NSABP B14 trial evaluating tamoxifen (tam) in axillary node negative, estrogen receptor positive tumors fewer breast recurrences were observed in patients treated with conservative surgery and radiation who received tam compared to the observation arm. An additional series, however, has suggested that tam adversely impacts on the cosmetic result. To further address these issues we compared the outcome of estrogen receptor positive tumors treated with conservative surgery and radiation with or without tam. Materials and Methods: From 1982 to 1991, 491 women with estrogen receptor positive stage I-II breast cancer underwent excisional biopsy, axillary dissection and radiation. The median age of the patient population was 60 years (range 39-85). The median followup was 5.3 years (range .1-12.8). 69% had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49%. The final margin of resection was negative in 64%, unknown in 18%, and close or positive in 19%. None of the patients received adjuvant chemotherapy. 154 patients received tam and 337 received no adjuvant therapy. Patients who received tam were more often axillary node positive (44% tam vs 5% no tam) and less often had unknown margins (9% tam vs 22% no tam). There were no significant differences for the 2 groups for median age, primary tumor size, histology, race, or use of reexcision. Results: The 5 yr act rate of breast recurrence was 4% for the tam patients compared to 7% for patients not receiving tam (p=.21). At 8 yrs, the breast recurrence rates were 4% for the tam patients compared to 11% for the no tam patients (p=.05). However, at 9 years the rates were 17% tam vs 14% no tam (p=.21). The benefit from tam in terms of a decreased 5 year actuarial breast recurrence rate was most evident for patients who did not have a reexcision (3% tam vs 10% no tam, p=.15), had unknown margins (7% tam vs 13% no tam, p=.37) or close margins (0% tam vs 11% no tam, p=.34

  8. Correlating Ki67 and other prognostic markers with Oncotype DX recurrence score in early estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Tan, Aaron C; Li, Bob T; Nahar, Kazi; Danieletto, Suzanne; Fong, Eva S; Currer, Trevor; Parasyn, Andrew; Middleton, Philip; Wong, Heidi; Smart, Denis; Rutovitz, Josie J; McCloud, Philip; Hughes, T Michael; Marx, Gavin M

    2017-09-29

    Decisions regarding adjuvant chemotherapy for early breast cancer are complex. Ki67 is increasingly used, in conjunction with conventional prognostic markers, to help decide the use of adjuvant chemotherapy for early breast cancer. Ki67 has been proposed as an economical alternative to Oncotype DX recurrence score (RS), which is a validated prognostic marker for disease recurrence and predictive marker for benefit from chemotherapy. This study aimed to determine in patients where conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy, whether Ki67 could be a substitute for RS. We reviewed all cases of luminal-type node-negative early breast cancer (T1-2, N0-1mi, M0, estrogen receptor positive, HER2 negative) referred for Oncotype DX testing by the multidisciplinary team at an Australian tertiary private hospital from 14th December 2006 to 31st December 2013, when conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy. RS was correlated with Ki67, along with other conventional prognostic markers including tumor size, grade, mitotic rate and lymphovascular invasion. Spearman's rank order correlation coefficient and Pearson product-moment correlation coefficient (r) were used for ordinal and continuous variables, respectively. A total of 58 patients were analyzed, median Ki67 was 15% (range 2-50%) and the median RS was 16 (range 3-65). There was no positive correlation between Ki67 and RS (r = 0.01, P = 0.93). No single conventional prognostic marker was shown to significantly correlate with RS, including tumor size (r = -0.02, P = 0.88), grade (r = 0.10, P = 0.44), mitotic rate (r = -0.07, P = 0.69) and lymphovascular invasion (r = -0.12, P = 0.39). Ki67 and conventional prognostic markers do not correlate with Oncotype DX RS. In the setting where conventional prognostic markers do not show a clear indication for or against adjuvant chemotherapy as determined by

  9. Bromine-80m-labeled estrogens: Auger-electron emitting, estrogen receptor-directed ligands with potential for therapy of estrogen receptor positive cancers

    International Nuclear Information System (INIS)

    DeSombre, E.R.; Mease, R.C.; Hughes, A.; Harper, P.V.; DeJesus, O.T.; Friedman, A.M.

    1988-01-01

    A triphenylbromoethylene, 1,1-bis(p-hydroxyphenyl)-2-bromo-2-phenylethylene, Br-BHPE, and a bromosteroidal estrogen, 17α- bromovinylestradiol, BrVE 2 , were labeled with the Auger electron emitting nuclide bromine-80m, prepared by the [p,n] reaction with 80 Se. To assess their potential as estrogen receptor (ER) directed therapeutic substrates the bromine-80m labeled estrogens were injected into immature female rats and the tissue distribution studied at 0.5 and 2 hours. Both radiobromoestrogens showed substantial diethylstilbesterol (DES)-inhibitable localization in the ER rich tissues, uterus, pituitary, ovary and vagina at both time points. While the percent dose per gram tissue was higher for the Br-BHPE, the BrVE 2 showed higher tissue to blood ratios, especially at 2 hr, reflecting the lower blood concentrations of radiobromine following administration of the steroidal bromoestrogen. Comparing intraperitoneal, intravenous and subcutaneous routes of administration for the radiobromine labeled Br-BHPE, the intraperitoneal route was particularly advantageous to provide maximum, DES-inhibitable concentrations in the peritoneal, ER-rich target organs, the uterus, ovary and vagina. While uterine concentrations after BrBHPE were from 10--48% dose/g and after BrVE 2 were 15--25% dose/g, similar treatment with /sup 80m/Br as sodium bromide showed uniform low concentrations in all tissues at about the levels seen in blood. The effective specific activity of [/sup 80m/Br]BrBHPE, assayed by specific binding to ER in rat uterine cytosol, was 8700 Ci/mmole. 23 refs., 9 figs., 2 tabs

  10. Gene expression signatures that predict outcome of tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients

    DEFF Research Database (Denmark)

    Lyng, Maria B; Lænkholm, Anne-Vibeke; Tan, Qihua

    2013-01-01

    BACKGROUND: Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant...... Tamoxifen mono-therapy. METHODOLOGY/PRINCIPAL FINDINGS: Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were...

  11. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042

    DEFF Research Database (Denmark)

    Milne, Roger L; Benítez, Javier; Nevanlinna, Heli

    2009-01-01

    BACKGROUND: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. METHODS: 2q35...

  12. 17β-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells

    International Nuclear Information System (INIS)

    Belkaid, Anissa; Duguay, Sabrina R.; Ouellette, Rodney J.; Surette, Marc E.

    2015-01-01

    To sustain cell growth, cancer cells exhibit an altered metabolism characterized by increased lipogenesis. Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the production of monounsaturated fatty acids that are essential for membrane biogenesis, and is required for cell proliferation in many cancer cell types. Although estrogen is required for the proliferation of many estrogen-sensitive breast carcinoma cells, it is also a repressor of SCD-1 expression in liver and adipose. The current study addresses this apparent paradox by investigating the impact of estrogen on SCD-1 expression in estrogen receptor-α-positive breast carcinoma cell lines. MCF-7 and T47D mammary carcinomas cells and immortalized MCF-10A mammary epithelial cells were hormone-starved then treated or not with 17β-estradiol. SCD-1 activity was assessed by measuring cellular monounsaturated/saturated fatty acid (MUFA/SFA) ratios, and SCD-1 expression was measured by qPCR, immunoblot, and immunofluorescence analyses. The role of SCD-1 in cell proliferation was measured following treatment with the SCD-1 inhibitor A959372 and following SCD-1 silencing using siRNA. The involvement of IGF-1R on SCD-1 expression was measured using the IGF-1R antagonist AG1024. The expression of SREBP-1c, a transcription factor that regulates SCD-1, was measured by qPCR, and by immunoblot analyses. 17β-estradiol significantly induced cell proliferation and SCD-1 activity in MCF-7 and T47D cells but not MCF-10A cells. Accordingly, 17β-estradiol significantly increased SCD-1 mRNA and protein expression in MCF-7 and T47D cells compared to untreated cells. Treatment of MCF-7 cells with 4-OH tamoxifen or siRNA silencing of estrogen receptor-α largely prevented 17β-estradiol-induced SCD-1 expression. 17β-estradiol increased SREBP-1c expression and induced the mature active 60 kDa form of SREBP-1. The selective SCD-1 inhibitor or siRNA silencing of SCD-1 blocked the 17β-estradiol-induced cell proliferation and increase in

  13. Comparison between Oncotype DX test and standard prognostic criteria in estrogen receptor positive early-stage breast cancer

    Directory of Open Access Journals (Sweden)

    Marcelo Roberto Pereira Freitas

    2011-09-01

    Full Text Available Objective: To compare the prognosis estimated by standardprognostic criteria versus the prognosis estimated by the OncotypeDX. Methods: A retrospective study was performed on 22 patientswith positive estrogen receptor, early-stage breast cancer whohad an Oncotype DX recurrence score available. Results: Kappavalue between Oncotype DX and standard prognostic criteriawas: Adjuvant! (K = 0.091, Adjuvant! (Transbig (K = 0.182 andNational Comprehensive Cancer Network (K = 0.091. The Fisher’sexact test did not show correlation between Oncotype and standardprognostic criteria. Conclusion: Standard prognostic criteria showedno correlation with Oncotype DX.

  14. Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer.

    Science.gov (United States)

    Fernandez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, Miguel

    2017-03-28

    PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%.

  15. Overexpression of the E2F target gene CENPI promotes chromosome instability and predicts poor prognosis in estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Thangavelu, Pulari U; Lin, Cheng-Yu; Vaidyanathan, Srividya; Nguyen, Thu H M; Dray, Eloise; Duijf, Pascal H G

    2017-09-22

    During cell division, chromosome segregation is facilitated by the mitotic checkpoint, or spindle assembly checkpoint (SAC), which ensures correct kinetochore-microtubule attachments and prevents premature sister-chromatid separation. It is well established that misexpression of SAC components on the outer kinetochores promotes chromosome instability (CIN) and tumorigenesis. Here, we study the expression of CENP-I, a key component of the HIKM complex at the inner kinetochores, in breast cancer, including ductal, lobular, medullary and male breast carcinomas. CENPI mRNA and protein levels are significantly elevated in estrogen receptor-positive (ER+) but not in estrogen receptor-negative (ER-) breast carcinoma. Well-established prognostic tests indicate that CENPI overexpression constitutes a powerful independent marker for poor patient prognosis and survival in ER+ breast cancer. We further demonstrate that CENPI is an E2F target gene. Consistently, it is overexpressed in RB1 -deficient breast cancers. However, CENP-I overexpression is not purely due to cell cycle-associated expression. In ER+ breast cancer cells, CENP-I overexpression promotes CIN, especially chromosome gains. In addition, in ER+ breast carcinomas the degree of CENPI overexpression is proportional to the level of aneuploidy and CENPI overexpression is one of the strongest markers for CIN identified to date. Our results indicate that overexpression of the inner kinetochore protein CENP-I promotes CIN and forecasts poor prognosis for ER+ breast cancer patients. These observations provide novel mechanistic insights and have important implications for breast cancer diagnostics and potentially therapeutic targeting.

  16. Lineage-Restricted Mammary Stem Cells Sustain the Development, Homeostasis, and Regeneration of the Estrogen Receptor Positive Lineage.

    Science.gov (United States)

    Van Keymeulen, Alexandra; Fioramonti, Marco; Centonze, Alessia; Bouvencourt, Gaëlle; Achouri, Younes; Blanpain, Cédric

    2017-08-15

    The mammary gland (MG) is composed of different cell lineages, including the basal and the luminal cells (LCs) that are maintained by distinct stem cell (SC) populations. LCs can be subdivided into estrogen receptor (ER) + and ER - cells. LCs act as the cancer cell of origin in different types of mammary tumors. It remains unclear whether the heterogeneity found in luminal-derived mammary tumors arises from a pre-existing heterogeneity within LCs. To investigate LC heterogeneity, we used lineage tracing to assess whether the ER + lineage is maintained by multipotent SCs or by lineage-restricted SCs. To this end, we generated doxycycline-inducible ER-rtTA mice that allowed us to perform genetic lineage tracing of ER + LCs and study their fate and long-term maintenance. Our results show that ER + cells are maintained by lineage-restricted SCs that exclusively contribute to the expansion of the ER + lineage during puberty and their maintenance during adult life. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer

    International Nuclear Information System (INIS)

    Fowble, Barbara; Fein, Douglas A.; Hanlon, Alexandra L.; Eisenberg, Burton L.; Hoffman, John P.; Sigurdson, Elin R.; Daly, Mary B.; Goldstein, Lori J.

    1996-01-01

    Purpose: To evaluate the impact of tamoxifen on breast recurrence, cosmesis, complications, overall and cause-specific survival in women with Stage I-II breast cancer and estrogen receptor positive tumors undergoing conservative surgery and radiation. Methods and Materials: From 1982 to 1991, 491 women with estrogen receptor positive Stage I-II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median age of the patient population was 60 years with 21% < 50 years of age. The median follow-up was 5.3 years (range 0.1 to 12.8). Sixty-nine percent had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49% and the final margin of resection was negative in 64%. One hundred fifty-four patients received tamoxifen and 337 patients received no adjuvant therapy. None of the patients received adjuvant chemotherapy. Results: There were no significant differences between the two groups for age, race, clinical tumor size, histology, the use of reexcision, or median total dose to the primary. Patients who received tamoxifen were more often axillary node positive (44% tamoxifen vs. 5% no tamoxifen), and, therefore, a greater percentage received treatment to the breast and regional nodes. The tamoxifen patients less often had unknown margins of resection (9% tamoxifen vs. 22% no tamoxifen). The 5-year actuarial breast recurrence rate was 4% for the tamoxifen patients compared to 7% for patients not receiving tamoxifen (p 0.21). Tamoxifen resulted in a modest decrease in the 5-year actuarial risk of a breast recurrence in axillary node-negative patients, in those with unknown or close margins of resection, and in those who underwent a single excision. Axillary node-positive patients had a clinically significant decrease in the 5-year actuarial breast recurrence rate (21 vs. 4%; p 0.08). The 5-year actuarial rate of distant metastasis was not significantly decreased by the addition of adjuvant tamoxifen in all

  18. Comparison of Radiologic Features of Triple-Negative and Estrogen Receptor/Progesteron Receptor Positive Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Joong; Kim, Keum Won; Kim, Dae Ho; Cho, Yong Jun; Hwang, Cheol Mog; Seo, Jae Young; Kim, Jin Suk; Yoon, Dae Sung [Dept. of Konyang University College of Medicine, Konyang University Hospital, Daejeon (Korea, Republic of); Kim, Gyu Soon [Dept. of Radiology, Eulji University College of Medicine, Eulji University Hospital, Daejeon (Korea, Republic of)

    2013-06-15

    To retrospectively investigate the imaging [mammographic, ultrasonographic (US), magnetic resonance (MR) imaging] features and standardized uptake values (SUV) in positron emission tomography (PET)/computed tomography (CT) of triple-negative breast cancers (TNBC) and to compare them with breast cancers that are either estrogen receptor (ER) positive or progesteron receptor (PR) positive. 155 breast cancers cases were identified in 134 women (mean age, 51 years; range, 31-86 years). Surgically confirmed TNBC (n = 27) and ER-positive/PR-positive breast cancers (n = 81) were included among them. Cancers were investigated with mammography (n = 81), US (n = 106), MR imaging (n = 34) and PET-CT (n = 59). Mammographic findings are identified by detection of characteristic masses and microcalcifications. US findings included tumor size, margin, tumor shape, calcification and posterior shadowing. MR findings included tumor size, shape, margin, internal enhancement, intratumoral signal intensity and kinetics. Peak SUVs (p-SUV) of breast cancers were evaluated in PET/CT. These findings were compared with TNBC and ER/PR positive groups. Mammographic findings had no significant association with the TNBC. High pathological grade (p < 0.05), larger than 2 cm in size, well-marginal mass, and round or oval-shaped (p < 0.05) is US were significantly associated with TNBC. In MR imaging, round mass shape (p < 0.05), well-circumscribed mass margin (p < 0.05), rim enhancement (p < 0.05), were significantly associated with TNBC. The peak SUV of TNBC tend to be higher than that of ER-positive/PR-positive breast cancer (7.95 {+-} 5.50 vs. 4.91 {+-} 3.00, p < 0.05). TNBC tend to have high pathological grade, are of a large, round and smooth mass with rim enhancement on MR and US. In addition to above features, PET-CT with SUV estimation can improve the accuracy of test through the evaluation of TNBC.

  19. Factors influencing the uptake of {sup 18}F-fluoroestradiol in patients with estrogen receptor positive breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Peterson, Lanell M. [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Department of Radiology, Seattle Cancer Care Alliance, Seattle WA (United States); Kurland, Brenda F. [Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA (United States); Link, Jeanne M. [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Schubert, Erin K. [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Department of Radiology, Seattle Cancer Care Alliance, Seattle WA (United States); Stekhova, Svetlana [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Linden, Hannah M. [Department of Medical Oncology, University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA (United States); Mankoff, David A., E-mail: dam@u.washington.edu [Department of Radiology, University of Washington Medical Center, Seattle WA (United States); Department of Radiology, Seattle Cancer Care Alliance, Seattle WA (United States)

    2011-10-15

    Introduction: {sup 18}F-Fluoroestradiol (FES) PET imaging provides a non-invasive method to measure estrogen receptor (ER) expression in tumors. Assessment of factors that could affect the quantitative level of FES uptake is important as part of the validation of FES PET for evaluating regional ER expression in breast cancer. Methods: This study examines FES uptake in tumors from 312 FES PET scans (239 patients) with documented ER+ primary breast cancer. FES uptake was compared to clinical and laboratory data, treatment prior to or at time of scan, and properties of FES and its metabolism and transport. Linear mixed models were used to explore univariate, threshold-based and multivariate associations. Results: Sex hormone-binding globulin (SHBG) was inversely associated with FES SUV. Average FES uptake did not differ by levels of plasma estradiol, age or rate of FES metabolism. FES tumor uptake was greater for patients with a higher body mass index (BMI), but this effect did not persist when SUV was corrected for lean body mass (LBM). In multivariate analysis, only plasma SHBG binding was an independent predictor of LBM-adjusted FES SUV. Conclusions: Calculation of FES SUV, possibly adjusted for LBM, should be sufficient to assess FES uptake for the purpose of inferring ER expression. Pre-menopausal estradiol levels do not appear to interfere with FES uptake. The availability and binding properties of SHBG influence FES uptake and should be measured. Specific activity did not have a clear influence on FES uptake, except perhaps at higher injected mass per kilogram. These results suggest that FES imaging protocols may be simplified without sacrificing the validity of the results.

  20. Prognostic value of Ki67 and p53 in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer: Validation of the cut-off value of the Ki67 labeling index as a predictive factor.

    Science.gov (United States)

    Ohara, Masahiro; Matsuura, Kazuo; Akimoto, Etsushi; Noma, Midori; Doi, Mihoko; Nishizaka, Takashi; Kagawa, Naoki; Itamoto, Toshiyuki

    2016-04-01

    The aim of this study was to evaluate the significance of the Ki67 labeling index and p53 status as prognostic and predictive indicators of operable estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Among 697 consecutive patients with primary breast cancer who underwent curative surgery between 2002 and 2013, 308 patients with ER-positive and HER2-negative breast cancer were assessed. The results of the multivariate Cox analysis demonstrated that a high Ki67 labeling index was significantly associated with a short recurrence-free interval (RFI) (p=0.004) and was marginally associated with a worse overall survival (p=0.074). A positive p53 status was not associated with worse outcomes. To validate the cut-off values of the Ki67 labeling index for identifying patients who may benefit from additional chemotherapy, prognostic factors were investigated in breast cancer patients treated postoperatively with endocrine therapy alone. Analysis of receiver operating characteristic curves demonstrated that a Ki67 labeling index cut-off of 20.0% was optimal for predicting recurrence among patients who did not receive adjuvant chemotherapy. The 5-year RFIs for patients with Ki67 Ki67 labeling index (≥20%) was significantly associated with large tumors (pKi67 labeling index ≥20%, lymph node metastasis and progesterone receptor negativity were significant worse prognostic factors for RFI (p=0.0333, 0.0116 and 0.0573, respectively). The Ki67 labeling index was found to be a useful prognostic factor in patients with ER-positive and HER2-negative breast cancer and the cut-off values of the Ki67 labeling index for making a decision regarding adjuvant treatment were validated.

  1. Endocrine sensitivity of the receptor-positive T61 human breast carcinoma serially grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Skovgaard Poulsen, H

    1985-01-01

    A study was made on the effect of ovariectomy, 17 beta-oestradiol, and tamoxifen on the oestrogen and progesterone receptor-positive T61 human breast carcinoma grown in nude mice. The effect of the treatment was evaluated by the specific growth delay calculated on the basis of Gompertz growth...

  2. Alterations in Circulating miRNA Levels following Early-Stage Estrogen Receptor-Positive Breast Cancer Resection in Post-Menopausal Women

    DEFF Research Database (Denmark)

    Kodahl, Annette R; Zeuthen, Pernille; Binder, Harald

    2014-01-01

    INTRODUCTION: Circulating microRNAs (miRNAs) exhibit remarkable stability and may serve as biomarkers in several clinical cancer settings. The aim of this study was to investigate changes in the levels of specific circulating miRNA following breast cancer surgery and evaluate whether these altera...... and could potentially be used to monitor whether all cancer cells have been removed at surgery and/or, subsequently, whether the patients develop recurrence.......INTRODUCTION: Circulating microRNAs (miRNAs) exhibit remarkable stability and may serve as biomarkers in several clinical cancer settings. The aim of this study was to investigate changes in the levels of specific circulating miRNA following breast cancer surgery and evaluate whether...... these alterations were also observed in an independent data set. METHODS: Global miRNA analysis was performed on prospectively collected serum samples from 24 post-menopausal women with estrogen receptor-positive early-stage breast cancer before surgery and 3 weeks after tumor resection using global LNA...

  3. Economic evaluation of 21-gene reverse transcriptase-polymerase chain reaction assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer in Japan.

    Science.gov (United States)

    Kondo, Masahide; Hoshi, Shu Ling; Ishiguro, Hiroshi; Yoshibayashi, Hiroshi; Toi, Masakazu

    2008-11-01

    The 21-gene reverse transcriptase-polymerase chain reaction assay with a patented algorithm is validated as a good predictor of prognosis and potential benefit from adjuvant chemotherapy for lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer, while its high cost raises concern about how to finance it. Cost-effectiveness analysis comparing prevalent National Comprehensive Cancer Network (NCCN) guideline/St Gallen recommendation-guided treatment with the assay-guided treatment is carried out with budget impact estimation in the context of Japan's health care system. Incremental cost-effectiveness ratios are estimated as 2,997,495 yen/QALY (26,065 US$/QALY) in the comparison between NCCN guided-treatment vs. the assay-guided treatment, and as 1,239,055 yen/QALY (10,774 US$/QALY) in the comparison between St Gallen guided-treatment vs. the assay-guided treatment. Budget impact is estimated as yen2,638 million (US$23 million) to yen3,225 million (US$28 million) per year. The routine use of the assay is indicated as cost-effective. And the budget impact could be judged as within fundable level.

  4. PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Sherene Loi

    Full Text Available The phosphatidylinositol 3' kinase (PI3K pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer and phosphorylated S6 (S240 immunohistochemistry (a substrate of mTOR. In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008 compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02. In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = -0.11, p = 0.37 but with relative change in phosphorlyated S6 (S240 (R = -0.46, p = 0.028. PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition

  5. A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study

    International Nuclear Information System (INIS)

    Gu, Ran; Long, Meijun; Chen, Kai; Chen, Lili; Xiao, Qiaozhen; Wu, Mei; Song, Erwei; Su, Fengxi; Jia, Weijuan; Zeng, Yunjie; Rao, Nanyan; Hu, Yue; Li, Shunrong; Wu, Jiannan; Jin, Liang; Chen, Lijuan

    2012-01-01

    In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. Toremifene may be a valid and

  6. A deep learning based strategy for identifying and associating mitotic activity with gene expression derived risk categories in estrogen receptor positive breast cancers.

    Science.gov (United States)

    Romo-Bucheli, David; Janowczyk, Andrew; Gilmore, Hannah; Romero, Eduardo; Madabhushi, Anant

    2017-06-01

    The treatment and management of early stage estrogen receptor positive (ER+) breast cancer is hindered by the difficulty in identifying patients who require adjuvant chemotherapy in contrast to those that will respond to hormonal therapy. To distinguish between the more and less aggressive breast tumors, which is a fundamental criterion for the selection of an appropriate treatment plan, Oncotype DX (ODX) and other gene expression tests are typically employed. While informative, these gene expression tests are expensive, tissue destructive, and require specialized facilities. Bloom-Richardson (BR) grade, the common scheme employed in breast cancer grading, has been shown to be correlated with the Oncotype DX risk score. Unfortunately, studies have also shown that the BR grade determined experiences notable inter-observer variability. One of the constituent categories in BR grading is the mitotic index. The goal of this study was to develop a deep learning (DL) classifier to identify mitotic figures from whole slides images of ER+ breast cancer, the hypothesis being that the number of mitoses identified by the DL classifier would correlate with the corresponding Oncotype DX risk categories. The mitosis detector yielded an average F-score of 0.556 in the AMIDA mitosis dataset using a 6-fold validation setup. For a cohort of 174 whole slide images with early stage ER+ breast cancer for which the corresponding Oncotype DX score was available, the distributions of the number of mitoses identified by the DL classifier was found to be significantly different between the high vs low Oncotype DX risk groups (P machine classifier trained to separate low/high Oncotype DX risk categories using the mitotic count determined by the DL classifier yielded a 83.19% classification accuracy. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

  7. Effect of metformin on estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells.

    Science.gov (United States)

    Amaral, Inês; Silva, Cláudia; Correia-Branco, Ana; Martel, Fátima

    2018-03-15

    This work aimed to investigate the effect of metformin on cellular glucose uptake and metabolism by breast cancer cells, as a mechanism contributing to its anticancer properties. Estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines were used as in vitro models of breast cancer. Short-term (26 min) exposure of MCF-7 and MDA-MB-231 cells to metformin inhibited uptake of 3 H-deoxy-D-glucose ( 3 H-DG). In contrast, long-term (24 h) exposure to metformin (5 μM-1 mM) concentration-dependently increased 3 H-DG uptake in both cell lines. This effect was associated with an increase in lactate production but was not associated with changes in GLUT1 mRNA expression. Long-term exposure of MCF-7 and MDA-MB-231 cells to metformin (5 μM-1 mM) concentration-dependently reduced cell viability and culture mass and slightly increased cell proliferation rates. Combination of metformin (1 mM) with the facilitative glucose transporter (GLUT) inhibitor kaempferol (30 μM) did not change the effect of metformin on culture growth. In conclusion, short-term exposure to metformin reduces cellular glucose uptake, probably by direct inhibition of GLUT1. However, after long-term exposure to metformin, cellular uptake of glucose is significantly increased, not associated to changes in GLUT1 transcription rates. We suggest that, in the long-term, metformin induces a compensatory increase in glucose uptake in response to cellular energy depletion resulting from its inhibitory effect on mitochondrial oxidative phosphorylation machinery. Metformin-induced dependence of breast cancer cells on glycolytic pathway, associated with an anticarcinogenic effect of the drug, provides a biochemical basis for the design of new therapeutic strategies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  8. A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells.

    Science.gov (United States)

    Motiani, Rajender K; Abdullaev, Iskandar F; Trebak, Mohamed

    2010-06-18

    Store-operated calcium (Ca(2+)) entry (SOCE) mediated by STIM/Orai proteins is a ubiquitous pathway that controls many important cell functions including proliferation and migration. STIM proteins are Ca(2+) sensors in the endoplasmic reticulum and Orai proteins are channels expressed at the plasma membrane. The fall in endoplasmic reticulum Ca(2+) causes translocation of STIM1 to subplasmalemmal puncta where they activate Orai1 channels that mediate the highly Ca(2+)-selective Ca(2+) release-activated Ca(2+) current (I(CRAC)). Whereas Orai1 has been clearly shown to encode SOCE channels in many cell types, the role of Orai2 and Orai3 in native SOCE pathways remains elusive. Here we analyzed SOCE in ten breast cell lines picked in an unbiased way. We used a combination of Ca(2+) imaging, pharmacology, patch clamp electrophysiology, and molecular knockdown to show that native SOCE and I(CRAC) in estrogen receptor-positive (ER(+)) breast cancer cell lines are mediated by STIM1/2 and Orai3 while estrogen receptor-negative (ER(-)) breast cancer cells use the canonical STIM1/Orai1 pathway. The ER(+) breast cancer cells represent the first example where the native SOCE pathway and I(CRAC) are mediated by Orai3. Future studies implicating Orai3 in ER(+) breast cancer progression might establish Orai3 as a selective target in therapy of ER(+) breast tumors.

  9. Endocrine sensitivity of the receptor-positive T61 human breast carcinoma serially grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Skovgaard Poulsen, H

    1985-01-01

    A study was made on the effect of ovariectomy, 17 beta-oestradiol, and tamoxifen on the oestrogen and progesterone receptor-positive T61 human breast carcinoma grown in nude mice. The effect of the treatment was evaluated by the specific growth delay calculated on the basis of Gompertz growth cur...... but is not a sufficiently clear marker to allow prediction of the endocrine sensitivity of individual breast tumours....

  10. Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast Cancer.

    Science.gov (United States)

    Schmid, Peter; Pinder, Sarah E; Wheatley, Duncan; Macaskill, Jane; Zammit, Charles; Hu, Jennifer; Price, Robert; Bundred, Nigel; Hadad, Sirwan; Shia, Alice; Sarker, Shah-Jalal; Lim, Louise; Gazinska, Patrycja; Woodman, Natalie; Korbie, Darren; Trau, Matt; Mainwaring, Paul; Gendreau, Steven; Lackner, Mark R; Derynck, Mika; Wilson, Timothy R; Butler, Hannah; Earl, Gemma; Parker, Peter; Purushotham, Arnie; Thompson, Alastair

    2016-06-10

    Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination:anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. Adding pictilisib to anastrozole significantly increases suppression

  11. Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

    International Nuclear Information System (INIS)

    Tutt, Andrew; Shu, Henry; Springall, Robert; Cane, Paul; McCallie, Blair; Kam-Morgan, Lauren; Anderson, Steve; Buerger, Horst; Gray, Joe; Bennington, James; Esserman, Laura; Wang, Alice; Hastie, Trevor; Broder, Samuel; Sninsky, John; Brandt, Burkhard; Waldman, Fred; Rowland, Charles; Gillett, Cheryl; Lau, Kit; Chew, Karen; Dai, Hongyue; Kwok, Shirley; Ryder, Kenneth

    2008-01-01

    Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times. 197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A 'metastasis score' (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women. A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14). The 14-gene signature is significantly

  12. CDO1 promoter methylation is a biomarker for outcome prediction of anthracycline treated, estrogen receptor-positive, lymph node-positive breast cancer patients.

    Science.gov (United States)

    Dietrich, Dimo; Krispin, Manuel; Dietrich, Jörn; Fassbender, Anne; Lewin, Jörn; Harbeck, Nadia; Schmitt, Manfred; Eppenberger-Castori, Serenella; Vuaroqueaux, Vincent; Spyratos, Frédérique; Foekens, John A; Lesche, Ralf; Martens, John W M

    2010-06-01

    Various biomarkers for prediction of distant metastasis in lymph-node negative breast cancer have been described; however, predictive biomarkers for patients with lymph-node positive (LNP) disease in the context of distinct systemic therapies are still very much needed. DNA methylation is aberrant in breast cancer and is likely to play a major role in disease progression. In this study, the DNA methylation status of 202 candidate loci was screened to identify those loci that may predict outcome in LNP/estrogen receptor-positive (ER+) breast cancer patients with adjuvant anthracycline-based chemotherapy. Quantitative bisulfite sequencing was used to analyze DNA methylation biomarker candidates in a retrospective cohort of 162 LNP/ER+ breast cancer patients, who received adjuvant anthracycline-based chemotherapy. First, twelve breast cancer specimens were analyzed for all 202 candidate loci to exclude genes that showed no differential methylation. To identify genes that predict distant metastasis, the remaining loci were analyzed in 84 selected cases, including the 12 initial ones. Significant loci were analyzed in the remaining 78 independent cases. Metastasis-free survival analysis was conducted by using Cox regression, time-dependent ROC analysis, and the Kaplan-Meier method. Pairwise multivariate regression analysis was performed by linear Cox Proportional Hazard models, testing the association between methylation scores and clinical parameters with respect to metastasis-free survival. Of the 202 loci analysed, 37 showed some indication of differential DNA methylation among the initial 12 patient samples tested. Of those, 6 loci were associated with outcome in the initial cohort (n = 84, log rank test, p Promoter DNA methylation of cysteine dioxygenase 1 (CDO1) was confirmed in univariate and in pairwise multivariate analysis adjusting for age at surgery, pathological T stage, progesterone receptor status, grade, and endocrine therapy as a strong and independent

  13. Prognostic significance of geminin expression levels in Ki67-high subset of estrogen receptor-positive and HER2-negative breast cancers.

    Science.gov (United States)

    Yagi, Tomoko; Inoue, Natsuko; Yanai, Ayako; Murase, Keiko; Imamura, Michiko; Miyagawa, Yoshimasa; Enomoto, Yukie; Nishimukai, Arisa; Takatsuka, Yuichi; Hirota, Seiichi; Akazawa, Kouhei; Miyoshi, Yasuo

    2016-03-01

    Indication for chemotherapy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers is determined on the basis of Ki67 expression level. However, since Ki67-high cancers are not necessarily sensitive to chemotherapy, identification of such patients who do not need chemotherapy is an important issue. We used immunohistochemical staining to examine the expression levels of ER, progesterone receptor (PgR), Ki67, and geminin, a marker of S to G2/M phases, in 80 ER-positive/HER2-negative breast cancers. The labeling indices of Ki67 and geminin were determined and cutoff values were set at 15 and 6 %, respectively. Ki67 and geminin expression levels were significantly associated with nuclear grade. In the Ki67-low subset, 26 out of 28 (92.9 %) cancers were geminin low and in the Ki67-high subset, 31 out of 52 (59.6 %) were geminin high. Distant disease-free survival (DDFS) of the geminin-high subset was significantly poorer than that of the geminin-low subset (P = 0.009). In the Ki67-low subset, only one patient showed recurrence. Metastasis was detected in eight out of 31 (25.8 %) patients in the geminin-high group of the Ki67-high subset, but no recurrence was observed in the geminin-low group of the Ki67-high subset. Geminin-high breast cancers are significantly associated with worse prognosis. Since poorer prognosis was recognized only in the geminin-high group in Ki67-high cancers, we speculate that geminin may be useful for identifying patients in the Ki67-high subset who can avoid unnecessary chemotherapy.

  14. Tamoxifen or letrozole versus standard methods for women with estrogen-receptor positive breast cancer undergoing oocyte or embryo cryopreservation in assisted reproduction

    NARCIS (Netherlands)

    Dahhan, Taghride; Balkenende, Eva; van Wely, Madelon; Linn, Sabine; Goddijn, Mariette

    2013-01-01

    Cryopreservation of oocytes or embryos preceded by controlled ovarian stimulation (COS) can increase the chance of future pregnancy in women with breast cancer who risk therapy-induced ovarian failure. In women with estrogen-receptor (ER) positive breast cancer, alternative COS protocols with

  15. Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer

    DEFF Research Database (Denmark)

    Sørensen, Kristina P; Thomassen, Mads; Tan, Qihua

    2013-01-01

    that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers (P = 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples (P = 0.0086, HR 1.985). In ER...

  16. Prognostic value of Bcl-2 in two independent populations of estrogen receptor positive breast cancer patients treated with adjuvant endocrine therapy

    DEFF Research Database (Denmark)

    Larsen, Mathilde S; Bjerre, Karsten; Giobbie-Hurder, Anita

    2012-01-01

    Estrogen receptor (ER) status is not an optimal marker for response to adjuvant endocrine therapy since approximately 30% of patients with ER-positive tumors eventually relapse. Bcl-2 is regulated by ER and may thus be considered as an indicator of ER activity and a candidate supplementary marker...

  17. A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer

    DEFF Research Database (Denmark)

    Baselga, José; Morales, Serafin M.; Awada, Ahmad

    2017-01-01

    Purpose: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). Methods: This randomized, multi...

  18. Effect of tamoxifen on the receptor-positive T61 and the receptor-negative T60 human breast carcinomas grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Vindeløv, L

    1985-01-01

    A study was made of the in vivo effect of the anti-oestrogen tamoxifen on the growth and cell cycle kinetics of the oestrogen and progesterone receptor-positive T61 human breast carcinoma and of the oestrogen and progesterone receptor-negative T60 human breast carcinoma grown in nude mice. The T61...

  19. Prediction of late distant recurrence in estrogen receptor positive breast cancer patients: prospective comparison of the Breast Cancer Index (BCI), Oncotype DX recurrence score, and IHC4 in TransATAC

    Science.gov (United States)

    Sgroi, Dennis C.; Sestak, Ivana; Cuzick, Jack; Zhang, Yi; Schnabel, Catherine A.; Schroeder, Brock; Erlander, Mark G.; Dunbier, Anita; Sidhu, Kally; Lopez-Knowles, Elena; Goss, Paul E.; Dowsett, Mitch

    2014-01-01

    SUMMARY BACKGROUND Greater than 50% of recurrences in estrogen receptor-positive (ER+) breast cancer occur after 5 years of adjuvant endocrine therapy. Biomarkers capable of improving the risk-benefit of extended adjuvant endocrine therapy for these late recurrences would be clinically valuable. We compared the prognostic ability of the Breast Cancer Index (BCI), Oncotype DX Recurrence Score (RS) and IHC4 for both early and late recurrence among patients with ER+, node negative (N0) disease within the ATAC clinical trial. METHODS BCI was performed from 1102 primary tumor samples from ER+ patients and two versions (BCI-C (primary) and BCI-L (secondary), based on cubic and linear combinations of the variables) were evaluated. RS and IHC4 values were previously derived. Prognostic discrimination for early (Research Program, Susan G. Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, Astrazeneca, NIHR Biomedical Research Centre at the Royal Marsden. PMID:24035531

  20. Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG)

    DEFF Research Database (Denmark)

    Skriver, Signe Korsgaard; Laenkholm, Anne-Vibeke; Rasmussen, Birgitte Bruun

    2018-01-01

    and received neoadjuvant chemotherapy. Eight patients received adjuvant chemotherapy due to lack of response. CONCLUSION: Neoadjuvant aromatase inhibitor therapy is an acceptable strategy in selected postmenopausal patients with ER-rich and HER2-negative early breast cancer with ductal histology and should......INTRODUCTION: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here......, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design. MATERIAL AND METHODS: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive...

  1. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR).

    Science.gov (United States)

    Kim, Jisun; Lim, Woosung; Kim, Eun-Kyu; Kim, Min-Kyoon; Paik, Nam-Sun; Jeong, Sang-Seol; Yoon, Jung-Han; Park, Chan Heun; Ahn, Sei Hyun; Kim, Lee Su; Han, Sehwan; Nam, Seok Jin; Kang, Han-Sung; Kim, Seung Il; Yoo, Young Bum; Jeong, Joon; Kim, Tae Hyun; Kang, Taewoo; Kim, Sung-Won; Jung, Yongsik; Lee, Jeong Eon; Kim, Ku Sang; Yu, Jong-Han; Chae, Byung Joo; Jung, So-Youn; Kang, Eunyoung; Choi, Su Yun; Moon, Hyeong-Gon; Noh, Dong-Young; Han, Wonshik

    2014-03-10

    Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. ClinicalTrials.gov Identifier NCT01589367.

  2. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

    Science.gov (United States)

    Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

    2017-05-02

    Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

  3. Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor-positive metastatic breast cancer patients with exceptional responses to capecitabine

    International Nuclear Information System (INIS)

    Levin, Maren K; Wang, Kai; Yelensky, Roman; Cao, Ying; Ramos, Corinne; Hoke, Nicholas; Pippen, John; Blum, Joanne L; Brooks, Barry; Palmer, Gary; Palma, Norma; Balasubramanian, Sohail; Ross, Jeffrey S; O’Shaughnessy, Joyce

    2015-01-01

    We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who had highly durable (≥5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin-fixed, paraffin-embedded tissue samples from patients’ primary (n = 4) or metastatic (n = 2) breast cancers were utilized for targeted next-generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy. Four patients received capecitabine in combination with paclitaxel; three of these continued single-agent capecitabine after stopping paclitaxel. Capecitabine was discontinued for progressive disease after a mean of 66 months in four patients (range 54–86 months), and two patients remain on therapy, having received capecitabine for >91 months and >122 months, respectively. Three patients’ cancers (50%) had likely functional alterations in DNA repair and chromatin remodeling genes, while three other patients’ cancers had variants of unknown significance in these pathways. Mutations in PIK3CA, amplifications of FGFR1 or ZNF703, or phosphorylation of HER family receptors and their downstream proteins did not preclude exceptional responses to capecitabine. None of the patients’ tumors harbored TP53 or PTEN mutations. Four of the patients had breast cancer tissue available for PTEN immunohistochemistry, and all four patients’ cancers were positive for PTEN. These surprising findings in a group of phenotypically similar patients with ER-positive, endocrine therapy-pretreated, HER2-negative metastases, are supported by preclinical data showing that sensitivity to 5-fluorouracil is enhanced by deficiencies in chromatin remodeling and homologous recombination genes. Our findings suggest that mutations that inactivate homologous recombination and/or chromatin remodeling genes within ER-positive, HER2-negative breast cancers may

  4. Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism

    Science.gov (United States)

    Goodman, C R; Sato, T; Peck, A R; Girondo, M A; Yang, N; Liu, C; Yanac, A F; Kovatich, A J; Hooke, J A; Shriver, C D; Mitchell, E P; Hyslop, T; Rui, H

    2016-01-01

    Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers. PMID:26096934

  5. High RAD51 mRNA expression characterize estrogen receptor-positive/progesteron receptor-negative breast cancer and is associated with patient's outcome.

    Science.gov (United States)

    Barbano, Raffaela; Copetti, Massimiliano; Perrone, Giuseppe; Pazienza, Valerio; Muscarella, Lucia Anna; Balsamo, Teresa; Storlazzi, Clelia Tiziana; Ripoli, Maria; Rinaldi, Monica; Valori, Vanna Maria; Latiano, Tiziana Pia; Maiello, Evaristo; Stanziale, Pietro; Carella, Massimo; Mangia, Alessandra; Pellegrini, Fabio; Bisceglia, Michele; Muda, Andrea Onetti; Altomare, Vittorio; Murgo, Roberto; Fazio, Vito Michele; Parrella, Paola

    2011-08-01

    Mutations in DNA double-strand breaks (DSB) repair genes are involved in the pathogenesis of hereditary mammary tumors, it is, however, still unclear whether defects in this pathway may play a role in sporadic breast cancer. In this study, we initially determined mRNA expression of 15 DSB related genes by reverse transcription quantitative polymerase chain reaction in paired normal tissue and cancer specimen from 20 breast cancer cases to classify them into homogeneous clusters. G22P1/ku70, ATR and RAD51 genes were differentially expressed in the three branches recognized by clustering analysis. In particular, a breast cancer subgroup characterized by high RAD51 mRNA levels and estrogen receptor (ER)-positive/progesteron receptor (PR)-negative phenotype was identified. This result was confirmed by the analysis of G22P1/ku70, ATR and RAD51 mRNA levels on paired normal and tumor specimens from an extended breast cancer cohort (n = 75). RAD51 mRNA levels were inversely associated with PR status (p = 0.02) and the highest levels were, indeed, detected in ER-positive/PR-negative tumors (p = 0.03). RAD51 immunostaining of a tissue microarray confirmed the inverse relationship between high RAD51 expression and negative PR status (p = 0.002), as well as, the association with ER-positive/PR-negative phenotype (p = 0.003). Interestingly, the analysis of microarray expression data from 295 breast cancers indicate that RAD51 increased mRNA expression is associated with higher risk of tumor relapse, distant metastases and worst overall survival (p = 0.015, p = 0.009 and p = 0.013 respectively). Our results suggest that RAD51 expression determination could contribute to a better molecular classification of mammary tumors and may represent a novel tool for evaluating postoperative adjuvant therapy for breast cancer patients. Copyright © 2010 UICC.

  6. Comparison of standardized uptake value of 18F-FDG-PET-CT with 21-gene recurrence score in estrogen receptor-positive, HER2-negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Sung Gwe Ahn

    Full Text Available We investigated the relationship between 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET-CT standardized uptake value (SUV and 21-gene recurrence score (RS in estrogen receptor (ER-positive/HER2-negative breast cancer.One hundred sixty-seven patients were identified among those who underwent preoperative 18F-FDG-PET-CT and had RS. Maximum SUV was obtained from 18F-FDG-PET-CT; the cut-off point was 4.The continuous RS and SUV correlated positively (Pearson's R = 0.555; P < 0.001. An inverse correlation was found between progesterone receptor (PR expression by reverse transcriptase-polymerase chain reaction, and SUV (Pearson's R = -0.408; P < 0.001. Good agreement between dichotomized RS (<26 vs. ≥26 and SUV (<4 vs. ≥4 was observed in 137 of 167 patients (82.0%; 95% confidence interval [CI], 76.2-87.9. Among patients with low SUV, 114 of 115 (99.1% [95% CI, 97.4-100.0] had tumors with lower RS (<26. Although 23 of 52 women (44.2% [95% CI, 30.7-57.7] with high SUV had higher RS (≥26, all 13 women with high RS (≥31 had high-SUV tumors. Most cases with disagreements between SUV and RS (n = 30 were classified as high SUV/lower RS (n = 29. The discordant group had higher grade or elevated Ki67 expression (≥20% compared with the low SUV/lower RS group (n = 109, but higher PR expression compared with the high SUV/higher RS group (n = 23. Multiple logistic regression analysis showed that high SUV were associated with higher RS (≥26.SUV, as a biologic parameter represented using a continuous variable, was found to associate with RS in ER-positive, HER2-negative breast cancer. Further studies may reveal the biology underlying the discordance between the markers.

  7. DCE-MRI texture analysis with tumor subregion partitioning for predicting Ki-67 status of estrogen receptor-positive breast cancers

    KAUST Repository

    Fan, Ming

    2017-12-08

    Breast tumor heterogeneity is related to risk factors that lead to worse prognosis, yet such heterogeneity has not been well studied.To predict the Ki-67 status of estrogen receptor (ER)-positive breast cancer patients via analysis of tumor heterogeneity with subgroup identification based on patterns of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Retrospective study.Seventy-seven breast cancer patients with ER-positive breast cancer were investigated, of whom 51 had low Ki-67 expression.T1 -weighted 3.0T DCE-MR images.Each tumor was partitioned into multiple subregions using three methods based on patterns of dynamic enhancement: 1) time to peak (TTP), 2) peak enhancement rate (PER), and 3) kinetic pattern clustering (KPC). In each tumor subregion, 18 texture features were computed.Univariate and multivariate logistic regression analyses were performed using a leave-one-out-based cross-validation (LOOCV) method. The partitioning results were compared with the same feature extraction methods across the whole tumor.In the univariate analysis, the best-performing feature was the texture statistic of sum variance in the tumor subregion with early TTP for differentiating between patients with high and low Ki-67 expression (area under the receiver operating characteristic curves, AUC = 0.748). Multivariate analysis showed that features from the tumor subregion associated with early TTP yielded the highest performance (AUC = 0.807) among the subregions for predicting the Ki-67 status. Among all regions, the tumor area with high PER at a precontrast MR image achieved the highest performance (AUC = 0.722), while the subregion that exhibited the highest overall enhancement rate based on KPC had an AUC of 0.731. These three models based on intratumoral texture analysis significantly (P < 0.01) outperformed the model using features from the whole tumor (AUC = 0.59).Texture analysis of intratumoral heterogeneity has the potential to serve as a valuable

  8. HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Wen-Tsung Huang

    2017-12-01

    Full Text Available Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+ breast cancer patients. Even though dysregulations of histone deacetylases (HDACs are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan–Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

  9. Ki67 expression in the primary tumor predicts for clinical benefit and time to progression on first-line endocrine therapy in estrogen receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Delpech, Y; Wu, Y; Hess, K R; Hsu, L; Ayers, M; Natowicz, R; Coutant, C; Rouzier, R; Barranger, E; Hortobagyi, G N; Mauro, D; Pusztai, L

    2012-09-01

    We examined whether baseline Ki67 expression in estrogen receptor-positive (ER+) primary breast cancer correlates with clinical benefit and time to progression on first-line endocrine therapy and survival in metastatic disease. Ki67 values and outcome information were retrieved from a prospectively maintained clinical database and validated against the medical records; 241 patients with metastatic breast cancer were included--who had ER+ primary cancer with known Ki67 expression level--and received first-line endocrine therapy for metastatic disease. Patients were assigned to low (25 %) Ki67 expression groups. Kaplan-Meier survival curves were plotted and multivariate analysis was performed to assess association between clinical and immunohistochemical variables and outcome. The clinical benefit rates were 81, 65, and 55 % in the low (n = 32), intermediate (n = 103), and high (n = 106) Ki67 expression groups (P = 0.001). The median times to progression on first-line endocrine therapy were 20.3 (95 % CI, 17.5-38.5), 10.8 (95 % CI, 8.9-18.8), and 8 (95 % CI, 6.1-11.1) months, respectively (P = 0.0002). The median survival times after diagnosis of metastatic disease were also longer for the low/intermediate compared to the high Ki67 group, 52 versus 30 months (P Ki67 expression in the primary tumor remained an independent adverse prognostic factor in metastatic disease (P = 0.001). Low Ki67 expression in the primary tumor is associated with higher clinical benefit and longer time to progression on first-line endocrine therapy and longer survival after metastatic recurrence.

  10. Cost-effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in women with early-stage estrogen- or progesterone-receptor-positive, axillary lymph-node negative breast cancer

    International Nuclear Information System (INIS)

    Hannouf, Malek B; Xie, Bin; Brackstone, Muriel; Zaric, Gregory S

    2012-01-01

    A 21-gene recurrence score (RS) assay may inform adjuvant systematic treatment decisions in women with early stage breast cancer. We sought to investigate the cost effectiveness of using the RS-assay versus current clinical practice (CCP) in women with early-stage estrogen- or progesterone-receptor-positive, axilliary lymph-node negative breast cancer (ER+/ PR + LN- ESBC) from the perspective of the Canadian public healthcare system. We developed a Markov model to project the lifetime clinical and economic consequences of ESBC. We evaluated adjuvant therapy separately in post- and pre-menopausal women with ER+/ PR + LN- ESBC. We assumed that the RS-assay would reclassify pre- and post-menopausal women among risk levels (low, intermediate and high) and guide adjuvant systematic treatment decisions. The model was parameterized using 7 year follow up data from the Manitoba Cancer Registry, cost data from Manitoba administrative databases, and secondary sources. Costs are presented in 2010 CAD. Future costs and benefits were discounted at 5%. The RS-assay compared to CCP generated cost-savings in pre-menopausal women and had an ICER of $60,000 per QALY gained in post-menopausal women. The cost effectiveness was most sensitive to the proportion of women classified as intermediate risk by the RS-assay who receive adjuvant chemotherapy and the risk of relapse in the RS-assay model. The RS-assay is likely to be cost effective in the Canadian healthcare system and should be considered for adoption in women with ER+/ PR + LN- ESBC. However, ongoing assessment and validation of the assay in real-world clinical practice is warranted

  11. Estrogen biosynthesis in human uterine adenomyosis

    International Nuclear Information System (INIS)

    Urabe, Mamoru; Yamamoto, Takara; Kitawaki, Jo; Honjo, Hideo; Okada, Hiroji

    1989-01-01

    Estrogen biosynthesis (aromatiase activity) was investigated in human adenomyosis tissue and compared with that of the normal myometrium, endometrium, and endometrical cancer tissues. Homogenates were incubated with [1,2,6,7- 3 H]androstenedione and NADPH at 37 deg. C for 1 h. After stopping the enzymatic reaction with ethyl acetate, [4- 14 C]estrone and [4- 14 C]estradiol-17β were added to the incubated sample. Estrone and estradiol were purified and identified by Bio-Rad AG1-X2 column chromatography, thin-layer chromatography and co-crystallization. Estrogen formed in the incubated sample was calculated from the 3 H/ 14 C ratio of the final crystal. The value for estrone formed from androstenedione was 52-132 fmol . h -1. g -1 wet weight. Aromatase activity in the adenomyosis tissues was higher than that in normal endometrial or myometrial tissues, but lower than that found in myometrial or endometrial tumour tissue. Furthermore, we investigated the effect of danazol, progresterone, and medroxyprogesterone acetate on adenomyosis cells in primary cultures. Aromatase activity in adenomyosis was blocked by danazol, but stimulated by progesterone and MPA. These results indicate that aromatase activity in adenomyosis may contribute to the growth of the ectopic endometrial tissue which occurs in this disease. (author)

  12. Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors

    NARCIS (Netherlands)

    L.J. Hofland (Leo); Q. Liu; P.M. van Koetsveld (Peter); J. Zuijderwijk; F. van der Ham (Frieda); R.R. de Krijger (Ronald); A. Schonbrunn; S.W.J. Lamberts (Steven)

    1999-01-01

    textabstractAlthough in situ hybridization has been used to examine the distribution of messenger RNA for somatostatin receptor subtypes (sst) in human tumors, the cellular localization of sst1 and sst2A receptors has not been reported. In this study, we describe the

  13. The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer

    DEFF Research Database (Denmark)

    Brunner, N; Spang-Thomsen, M; Cullen, K

    1996-01-01

    Endocrine therapy is one of the principal treatment modalities of breast cancer, both in an adjuvant setting and in advanced disease. The T61 breast cancer xenograft described here provides an experimental model of the effects of estrogen treatment at a molecular level. T61 is an estrogen receptor...... positive tumor which was originally derived from a T1N0M0 invasive ductal cancer and has been carried as a serially transplanted xenograft in nude mice. T61 is a hormone sensitive tumor whose growth is suppressed by both estrogen and tamoxifen, in contrast to other estrogen receptor positive tumors...... growth is also inhibited in animals treated with a monoclonal antibody which blocks binding of ligand to the IGF-I receptor, which mediates the mitogenic signal of bound IGF-II through autophosphorylation of its intracellular tyrosine kinase domain. These results demonstrate the utility of the T61 model...

  14. The expression of estrogen receptors and the effects of estrogen on human periodontal ligament cells.

    Science.gov (United States)

    Cao, M; Shu, L; Li, J; Su, J; Zhang, W; Wang, Q; Guo, T; Ding, Y

    2007-06-01

    Osteoporotic women exhibit high frequency of alveolar bone loss and low bone density. Estrogen deficiency, which is vital in the pathogenesis of postmenopausal osteoporosis, has received increasing attention in the studies related to the periodontal diseases. Similar to most hormones, estrogen exerts its influence by binding to specific receptors, estrogen receptor (ER)-alpha and -beta. The periodontal ligament cells (PDLcs) are very important in maintaining the integrity of the periodontal tissue, which is the connective tissue located between the alveolar bone and the root surface of tooth. In this study, we evaluated the effects of estrogen deficiency on the alveolar bone in ovariectomized rats by histometric measurement of attachment level in vivo. Using the reverse transcriptase polymerase chain reaction (RT-PCR) and Western-blot procedure, we also detected mRNA and protein products of ERs and investigated the effects of estrogen on bone-forming capability by monitoring alkaline phosphatase (ALP) activity and osteocalcin production in cultured human PDLcs. Our results demonstrated that both ER-alpha and -beta were expressed in PDLcs. Moreover, when exposed to 17-beta estradiol, PDLcs exhibited positive modulation on ALP activity and osteocalcin production. The study suggests that estrogen and ERs may play an important role in periodontal diseases. (c) 2007 Prous Science. All rights reserved.

  15. The Endocrine Role of Estrogens on Human Male Skeleton

    Directory of Open Access Journals (Sweden)

    Vincenzo Rochira

    2015-01-01

    Full Text Available Before the characterization of human and animal models of estrogen deficiency, estrogen action was confined in the context of the female bone. These interesting models uncovered a wide spectrum of unexpected estrogen actions on bone in males, allowing the formulation of an estrogen-centric theory useful to explain how sex steroids act on bone in men. Most of the principal physiological events that take place in the developing and mature male bone are now considered to be under the control of estrogen. Estrogen determines the acceleration of bone elongation at puberty, epiphyseal closure, harmonic skeletal proportions, the achievement of peak bone mass, and the maintenance of bone mass. Furthermore, it seems to crosstalk with androgen even in the determination of bone size, a more androgen-dependent phenomenon. At puberty, epiphyseal closure and growth arrest occur when a critical number of estrogens is reached. The same mechanism based on a critical threshold of serum estradiol seems to operate in men during adulthood for bone mass maintenance via the modulation of bone formation and resorption in men. This threshold should be better identified in-between the ranges of 15 and 25 pg/mL. Future basic and clinical research will optimize strategies for the management of bone diseases related to estrogen deficiency in men.

  16. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.

    Science.gov (United States)

    Fu, Xiaoyong; Creighton, Chad J; Biswal, Nrusingh C; Kumar, Vijetha; Shea, Martin; Herrera, Sabrina; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Nanda, Sarmistha; Giuliano, Mario; Morrison, Gladys; Nardone, Agostina; Karlin, Kristen L; Westbrook, Thomas F; Heiser, Laura M; Anur, Pavana; Spellman, Paul; Guichard, Sylvie M; Smith, Paul D; Davies, Barry R; Klinowska, Teresa; Lee, Adrian V; Mills, Gordon B; Rimawi, Mothaffar F; Hilsenbeck, Susan G; Gray, Joe W; Joshi, Amit; Osborne, C Kent; Schiff, Rachel

    2014-09-11

    Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance. Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy. Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression. Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.

  17. Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in the United States.

    Science.gov (United States)

    Xie, Jipan; Diener, Melissa; De, Gourab; Yang, Hongbo; Wu, Eric Q; Namjoshi, Madhav

    2013-01-01

    To estimate the budget impact of everolimus as the first and second treatment option after letrozole or anastrozole (L/A) failure for post-menopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). Pharmacy and medical budget impacts (2011 USD) were estimated over the first year of everolimus use in HR+, HER2- ABC from a US payer perspective. Epidemiology data were used to estimate target population size. Pre-everolimus entry treatment options included exemestane, fulvestrant, and tamoxifen. Pre- and post-everolimus entry market shares were estimated based on market research and assumptions. Drug costs were based on wholesale acquisition cost. Patients were assumed to be on treatment until progression or death. Annual medical costs were calculated as the average of pre- and post-progression medical costs weighted by the time in each period, adjusted for survival. One-way and two-way sensitivity analyses were conducted to assess the model robustness. In a hypothetical 1,000,000 member plan, 72 and 159 patients were expected to be candidates for everolimus treatment as first and second treatment option, respectively, after L/A failure. The total budget impact for the first year post-everolimus entry was $0.044 per member per month [PMPM] (pharmacy budget: $0.058 PMPM; medical budget: -$0.014 PMPM), assuming 10% of the target population would receive everolimus. The total budget impacts for the first and second treatment options after L/A failure were $0.014 PMPM (pharmacy budget: $0.018; medical budget: -$0.004) and $0.030 PMPM (pharmacy budget: $0.040; medical budget: -$0.010), respectively. Results remained robust in sensitivity analyses. Assumptions about some model input parameters were necessary and may impact results. Increased pharmacy costs for HR+, HER2- ABC following everolimus entry are expected to be partially offset by reduced medical service costs. Pharmacy and total

  18. Utility of {sup 18}F-fluoroestradiol ({sup 18}F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Frank I. [National Cancer Institute, NIH, Cancer Imaging Program, Bethesda, MD (United States); National Cancer Institute, Molecular Imaging Program, Bethesda, MD (United States); Gonzalez, E.M.; Kurdziel, K.A.; Ton, A.; Turkbey, B.; Choyke, P.L.; Lindenberg, M.L. [National Cancer Institute, Molecular Imaging Program, Bethesda, MD (United States); Kummar, S.; Do, K.; Collins, J.M.; Doroshow, J.H. [National Cancer Institute, Division of Cancer Treatment and Diagnosis and Center for Cancer Research, Bethesda, MD (United States); Shih, J. [National Cancer Institute, NIH, Biometric Research Program, Bethesda, MD (United States); Adler, S. [Leidos Biomedical Research, Inc., Clinical Research Directorate/Clinical Monitoring Research Program, Frederick, MD (United States); Jacobs, P.M. [National Cancer Institute, NIH, Cancer Imaging Program, Bethesda, MD (United States); Bhattacharyya, S. [Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD (United States); Chen, A.P. [National Cancer Institute, Early Clinical Trials Development Program, DCTD, Bethesda, MD (United States)

    2017-03-15

    Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. {sup 18}F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes {sup 18}F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with {sup 18}F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with {sup 18}F-FES 1-5 days post administration of Z-endoxifen. Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy. (orig.)

  19. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-α with BCAR1 and Traf6

    International Nuclear Information System (INIS)

    Robinson, Lisa J.; Yaroslavskiy, Beatrice B.; Griswold, Reed D.; Zadorozny, Eva V.; Guo, Lida; Tourkova, Irina L.; Blair, Harry C.

    2009-01-01

    The effects of estrogen on osteoclast survival and differentiation were studied using CD14-selected mononuclear osteoclast precursors from peripheral blood. Estradiol at ∼ 1 nM reduced RANKL-dependent osteoclast differentiation by 40-50%. Osteoclast differentiation was suppressed 14 days after addition of RANKL even when estradiol was withdrawn after 18 h. In CD14+ cells apoptosis was rare and was not augmented by RANKL or by 17-β-estradiol. Estrogen receptor-α (ERα) expression was strongly down-regulated by RANKL, whether or not estradiol was present. Mature human osteoclasts thus cannot respond to estrogen via ERα. However, ERα was present in CD14+ osteoclast progenitors, and a scaffolding protein, BCAR1, which binds ERα in the presence of estrogen, was abundant. Immunoprecipitation showed rapid (∼ 5 min) estrogen-dependent formation of ERα-BCAR1 complexes, which were increased by RANKL co-treatment. The RANKL-signaling intermediate Traf6, which regulates NF-κB activity, precipitated with this complex. Reduction of NF-κB nuclear localization occurred within 30 min of RANKL stimulation, and estradiol inhibited the phosphorylation of IκB in response to RANKL. Inhibition by estradiol was abolished by siRNA knockdown of BCAR1. We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ERα.

  20. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-{alpha} with BCAR1 and Traf6

    Energy Technology Data Exchange (ETDEWEB)

    Robinson, Lisa J., E-mail: robinsonlj@msx.upmc.edu [Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Yaroslavskiy, Beatrice B.; Griswold, Reed D.; Zadorozny, Eva V.; Guo, Lida; Tourkova, Irina L. [Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Blair, Harry C. [Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Veteran' s Affairs Medical Center, Pittsburgh, PA 15243 (United States)

    2009-04-15

    The effects of estrogen on osteoclast survival and differentiation were studied using CD14-selected mononuclear osteoclast precursors from peripheral blood. Estradiol at {approx} 1 nM reduced RANKL-dependent osteoclast differentiation by 40-50%. Osteoclast differentiation was suppressed 14 days after addition of RANKL even when estradiol was withdrawn after 18 h. In CD14+ cells apoptosis was rare and was not augmented by RANKL or by 17-{beta}-estradiol. Estrogen receptor-{alpha} (ER{alpha}) expression was strongly down-regulated by RANKL, whether or not estradiol was present. Mature human osteoclasts thus cannot respond to estrogen via ER{alpha}. However, ER{alpha} was present in CD14+ osteoclast progenitors, and a scaffolding protein, BCAR1, which binds ER{alpha} in the presence of estrogen, was abundant. Immunoprecipitation showed rapid ({approx} 5 min) estrogen-dependent formation of ER{alpha}-BCAR1 complexes, which were increased by RANKL co-treatment. The RANKL-signaling intermediate Traf6, which regulates NF-{kappa}B activity, precipitated with this complex. Reduction of NF-{kappa}B nuclear localization occurred within 30 min of RANKL stimulation, and estradiol inhibited the phosphorylation of I{kappa}B in response to RANKL. Inhibition by estradiol was abolished by siRNA knockdown of BCAR1. We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ER{alpha}.

  1. Environmental impact of estrogens on human, animal and plant life: A critical review.

    Science.gov (United States)

    Adeel, Muhammad; Song, Xiaoming; Wang, Yuanyuan; Francis, Dennis; Yang, Yuesuo

    2017-02-01

    Since the inception of global industrialization, steroidal estrogens have become an emerging and serious concern. Worldwide, steroid estrogens including estrone, estradiol and estriol, pose serious threats to soil, plants, water resources and humans. Indeed, estrogens have gained notable attention in recent years, due to their rapidly increasing concentrations in soil and water all over the world. Concern has been expressed regarding the entry of estrogens into the human food chain which in turn relates to how plants take up and metabolism estrogens. In this review we explore the environmental fate of estrogens highlighting their release through effluent sources, their uptake, partitioning and physiological effects in the ecological system. We draw attention to the potential risk of intensive modern agriculture and waste disposal systems on estrogen release and their effects on human health. We also highlight their uptake and metabolism in plants. We use MEDLINE and other search data bases for estrogens in the environment from 2005 to the present, with the majority of our sources spanning the past five years. Published acceptable daily intake of estrogens (μg/L) and predicted no effect concentrations (μg/L) are listed from published sources and used as thresholds to discuss reported levels of estrogens in the aquatic and terrestrial environments. Global levels of estrogens from river sources and from Waste Water Treatment Facilities have been mapped, together with transport pathways of estrogens in plants. Estrogens at polluting levels have been detected at sites close to waste water treatment facilities and in groundwater at various sites globally. Estrogens at pollutant levels have been linked with breast cancer in women and prostate cancer in men. Estrogens also perturb fish physiology and can affect reproductive development in both domestic and wild animals. Treatment of plants with steroid estrogen hormones or their precursors can affect root and shoot

  2. A comparative study of protein patterns of human estrogen receptor positive (MCF-7) and negative (MDA-MB-231) breast cancer cell lines

    Czech Academy of Sciences Publication Activity Database

    Flodrová, Dana; Toporová, L.; Macejová, D.; Laštovičková, Markéta; Brtko, J.; Bobálová, Janette

    2016-01-01

    Roč. 35, č. 3 (2016), s. 387-392 ISSN 0231-5882 Grant - others:Akademie věd - GA AV ČR(CZ) SAV-15-01 Program:Bilaterální spolupráce Institutional support: RVO:68081715 Keywords : cell line * breast cancer * protein * mass spectrometry Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 1.170, year: 2016

  3. Human estrogen sulfotransferase (SULT1E1) pharmacogenomics: gene resequencing and functional genomics

    OpenAIRE

    Adjei, Araba A; Thomae, Bianca A; Prondzinski, Janel L; Eckloff, Bruce W; Wieben, Eric D; Weinshilboum, Richard M

    2003-01-01

    Estrogens are used as drugs and estrogen exposure is a risk factor for hormone-dependent diseases such as breast cancer. Sulfate conjugation is an important pathway for estrogen metabolism. The sulfotransferase (SULT) enzyme SULT1E1 has the lowest Km values for estrogens and catecholestrogens of the 10 known human SULT isoforms.We previously cloned and characterized the human SULT1E1 cDNA and gene as steps toward pharmacogenetic studies. In the present experiments, we set out to determine whe...

  4. Estrogenic effects of fusarielins in human breast cancer cell lines

    DEFF Research Database (Denmark)

    Søndergaard, Teis; Klitgaard, Louise Graabæk; Purup, Stig

    2012-01-01

    from fungi that bind to the estrogen receptors and induce an estrogenic response in targeted cells. All four tested fusarielins stimulate MCF-7 cell proliferation with fusarielin H as the most potent, able to stimulate cell proliferation 4-fold in a resazurin metabolism assay at 25 μM. MDA-MB-231 cells...... without the estrogen receptor-α and MCF-10a cells without estrogen receptors were not stimulated by fusarielins. Furthermore, the stimulation was prevented in MCF-7 cells when fusarielins were incubated in the presence of the estrogen receptor antagonist fulvestrant. These observations suggest...

  5. Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study.

    Science.gov (United States)

    Martin, Miguel; Brase, Jan C; Ruiz, Amparo; Prat, Aleix; Kronenwett, Ralf; Calvo, Lourdes; Petry, Christoph; Bernard, Philip S; Ruiz-Borrego, Manuel; Weber, Karsten E; Rodriguez, César A; Alvarez, Isabel M; Segui, Miguel A; Perou, Charles M; Casas, Maribel; Carrasco, Eva; Caballero, Rosalía; Rodriguez-Lescure, Alvaro

    2016-02-01

    There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2-) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2- patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan-Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87 %; ROR-P 89 %; EP 93 %). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88 %; ROR-PT 92 %; EPclin 100 %). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2- BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability.

  6. Epoxide hydrolase affects estrogen production in the human ovary.

    Science.gov (United States)

    Hattori, N; Fujiwara, H; Maeda, M; Fujii, S; Ueda, M

    2000-09-01

    To investigate the mechanisms of ovarian cell differentiation, we raised a new monoclonal antibody, HCL-3, which reacted with human luteal cells. It also reacted with human and porcine hepatocytes. The immunoaffinity-purified HCL-3 antigen from human corpora lutea (CL) was shown to be a 46-kDa protein. The N-terminal 22 amino acids of the 46-kDa protein from porcine liver exhibited high homology (82%) to human microsomal epoxide hydrolase (mEH). The purified HCL-3 antigen from human CL or porcine liver showed EH enzyme activity, confirming that HCL-3 antigen is identical to mEH, which is reported to detoxify the toxic substrates in the liver. In human follicles, mEH was immunohistochemically detected on granulosa and theca interna cells. In the menstrual and pregnant CL, mEH was also expressed on large and small luteal cells. A competitive inhibitor of EH, 1,2-epoxy-3,3,3-trichloropropane, inhibited the conversion of estradiol from testosterone by granulosa cells cultured in vitro, indicating the involvement of mEH in ovarian estrogen production. Because anticonvulsant sodium valproate and its analogues were reported to inhibit EH enzyme activity, these findings provide a new insight into the etiology of endocrine disorders that are frequently observed among epileptic patients taking anticonvulsant drugs.

  7. The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer

    DEFF Research Database (Denmark)

    Brunner, N; Spang-Thomsen, M; Cullen, K

    1996-01-01

    positive tumor which was originally derived from a T1N0M0 invasive ductal cancer and has been carried as a serially transplanted xenograft in nude mice. T61 is a hormone sensitive tumor whose growth is suppressed by both estrogen and tamoxifen, in contrast to other estrogen receptor positive tumors...... such as MCF-7 which are stimulated by estrogen. Molecular studies have demonstrated that T61 expresses easily detectable levels of mRNA for a number of peptide growth factors, including transforming growth factor alpha (TGF-alpha) and insulin-like growth factors I and II (IGF-I and IGF......-II), but not transforming growth factor beta-I (TGF-beta1). Of these, IGF-II is the only peptide whose expression is altered by endocrine therapy. Treatment of T61-bearing nude mice with physiologic doses of estrogen is accompanied by loss of IGF-II mRNA expression within 24 hours, and rapid regression of tumor. T61 tumor...

  8. Estrogen modulates inhibitory control in healthy human females: evidence from the stop-signal paradigm

    NARCIS (Netherlands)

    Colzato, L.S.; Hertsig, G.; van den Wildenberg, W.P.M.; Hommel, B.

    2010-01-01

    Animal studies point to a role of estrogen in explaining gender differences in striatal dopaminergic functioning, but evidence from human studies is still lacking. Given that dopamine is crucial for controlling and organizing goal-directed behavior, estrogen may have a specific impact on cognitive

  9. Expression and function of the human estrogen receptor in yeast

    International Nuclear Information System (INIS)

    White, J.H.; Metzger, D.; Chambon, P.

    1988-01-01

    Gene expression in eukaryotes is regulated at many levels. Moreover, there is increasing evidence that the basic control mechanisms of transcription initiation have been conserved across the range of eukaryotes from yeast to man. In vertebrates, the nuclear receptors, whose activity is dependent on the binding of specific ligands, stimulate transcription by interacting with specific cis-acting sequences and display all of the hallmarks of inducible enhancer factors. Alignment of their amino acid sequences indicates that they are composed of a series of conserved domains. The domain structure of the human estrogen receptor (hER) is typical of receptor proteins. Region C, containing two putative zinc fingers, comprises the DNA-binding domain responsible for specific recognition of estrogen response elements (ERE). Region E contains the hormone-binding domain and domain(s) responsible for transcription activation. A mutant of the hER, called HE15, which lacks the hormone-binding domain, binds DNA in vivo and in vitro but activates transcription only poorly in a constitutive manner in vivo in HeLa cells. A series of studies have demonstrated that the hormone- and DNA-binding domains of the nuclear receptors function independently. Chimeric proteins consisting of the DNA-binding domain of yeast GAL4 coupled to the hormone-binding domains of either the hER or glucocorticoid receptor element (GRE) will stimulate transcription in HeLa cells when bound to a UAS. Taken together, these results demonstrate that the hER and other nuclear receptors, as well as GAL4 and GCN4 proteins of yeast, consist of discrete and separable DNA-binding and transcription-activation functions. To investigate these striking parallels further, the authors have expressed the hER in the yeast Saccharomyces cerevisiae and have analyzed its hormone- and DNA-binding properties in vitro and its ability to stimulate transcription in vivo

  10. Preliminary Genetic Imaging Study of the Association between Estrogen Receptor-α Gene Polymorphisms and Harsh Human Maternal Parenting

    OpenAIRE

    Lahey, Benjamin B.; Michalska, Kalina J.; Liu, Chunyu; Chen, Qi; Hipwell, Alison E.; Waldman, Irwin D.; Decety, Jean

    2012-01-01

    A failure of neural changes initiated by the estrogen surge in late pregnancy to reverse the valence of infant stimuli from aversive to rewarding is associated with dysfunctional maternal behavior in nonhuman mammals. Estrogen receptor-α plays the crucial role in mediating these neural effects of estrogen priming. This preliminary study examines associations between estrogen receptor-α gene polymorphisms and human maternal behavior. Two polymorphisms were associated with human negative matern...

  11. Effect of estrogen withdrawal on energy-rich phosphates and prediction of estrogen dependence monitored by in vivo 31P magnetic resonance spectroscopy of four human breast cancer xenografts

    DEFF Research Database (Denmark)

    Kristensen, C A; Kristjansen, P E; Brünner, N

    1995-01-01

    The effect of estrogen withdrawal on energy metabolism was studied in four human breast cancer xenografts: the estrogen-dependent MCF-7 and ZR75-1 and the estrogen-independent ZR75/LCC-3 and MDA-MB-231. The tumors were grown in ovariectomized nude mice with a s.c. implanted estrogen pellet. After...

  12. Identification, cloning, and expression of human estrogen receptor-α36, a novel variant of human estrogen receptor-α66

    International Nuclear Information System (INIS)

    Wang Zhaoyi; Zhang Xintian; Shen Peng; Loggie, Brian W.; Chang Yunchao; Deuel, Thomas F.

    2005-01-01

    The identification and subsequent cloning of the 66-kDa human estrogen receptor (here termed hER-α66), its 46-kDa splice variant hER-α46, and the closely related hER-β have had a profound impact on the generation of new understanding of estrogen-mediated functions and led to progress in diagnosis and treatment of human breast cancer. However, a persistent problem has been that not all findings previously reported in estrogen-stimulated cell proliferation can be explained through the known properties of the different estrogen receptors described. As the consequence of a search for alternative mechanisms to account for these different findings, we have now identified, cloned, and expressed in HEK 293 cells a previously unrecognized 36-kDa variant of hER-α66, termed hER-α36. hER-α36 differs from hER-α66 since it lacks both transcriptional activation domains (AF-1 and AF-2) but it retains the DNA-binding domain, and partial dimerization and ligand-binding domains of hER-α66. It also contains three myristoylation sites postulated to direct ER-α36 to the plasma membrane. It is concluded that ER-α36 is a unique variant of ER-α66; ER-α36 is predicted to function as a dominant-negative effector of hER-α66-mediated estrogen-responsive gene pathways and has the potential to trigger membrane-initiated mitogenic estrogen signaling

  13. Pomegranate extract demonstrate a selective estrogen receptor modulator profile in human tumor cell lines and in vivo models of estrogen deprivation.

    Science.gov (United States)

    Sreeja, Sreekumar; Santhosh Kumar, Thankayyan R; Lakshmi, Baddireddi S; Sreeja, Sreeharshan

    2012-07-01

    Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands exhibiting tissue-specific agonistic or antagonistic biocharacter and are used in the hormonal therapy for estrogen-dependent breast cancers. Pomegranate fruit has been shown to exert antiproliferative effects on human breast cancer cells in vitro. In this study, we investigated the tissue-specific estrogenic/antiestrogenic activity of methanol extract of pericarp of pomegranate (PME). PME was evaluated for antiproliferative activity at 20-320 μg/ml on human breast (MCF-7, MDA MB-231) endometrial (HEC-1A), cervical (SiHa, HeLa), ovarian (SKOV3) carcinoma and normal breast fibroblast (MCF-10A) cells. Competitive radioactive binding studies were carried out to ascertain whether PME interacts with ER. The reporter gene assay measured the estrogenic/antiestrogenic activity of PME in MCF-7 and MDA MB-231 cells transiently transfected with plasmids coding estrogen response elements with a reporter gene (pG5-ERE-luc) and wild-type ERα (hEG0-ER). PME inhibited the binding of [³H] estradiol to ER and suppressed the growth and proliferation of ER-positive breast cancer cells. PME binds ER and down-regulated the transcription of estrogen-responsive reporter gene transfected into breast cancer cells. The expressions of selected estrogen-responsive genes were down-regulated by PME. Unlike 17β-estradiol [1 mg/kg body weight (BW)] and tamoxifen (10 mg/kg BW), PME (50 and 100 mg/kg BW) did not increase the uterine weight and proliferation in ovariectomized mice and its cardioprotective effects were comparable to that of 17β-estradiol. In conclusion, our findings suggest that PME displays a SERM profile and may have the potential for prevention of estrogen-dependent breast cancers with beneficial effects in other hormone-dependent tissues. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Molecular analysis of human endometrium: Short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling

    NARCIS (Netherlands)

    P. Hanifi-Moghaddam (Payman); B. Boers-Sijmons (Bianca); A.H.A. Klaassens (Anet); F.H. van Wijk (Heidy); M.A. den Bakker (Michael); M.C. Ott; G.L. Shipley; H.A.M. Verheul (Herman); H.J. Kloosterboer (Helenius); C.W. Burger (Curt); L.J. Blok (Leen)

    2007-01-01

    textabstractTibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current

  15. Effect of estrogen withdrawal on energy-rich phosphates and prediction of estrogen dependence monitored by in vivo 31P magnetic resonance spectroscopy of four human breast cancer xenografts

    DEFF Research Database (Denmark)

    Kristensen, C A; Kristjansen, P E; Brünner, N

    1995-01-01

    The effect of estrogen withdrawal on energy metabolism was studied in four human breast cancer xenografts: the estrogen-dependent MCF-7 and ZR75-1 and the estrogen-independent ZR75/LCC-3 and MDA-MB-231. The tumors were grown in ovariectomized nude mice with a s.c. implanted estrogen pellet. After......:Pi ratio in the two estrogen-dependent xenografts, whereas this ratio remained unchanged in the estrogen-independent tumors. In ZR75/LCC-3 tumors a slight decrease in nucleoside triphosphate:Pi was observed following onset of estrogen stimulation after initial growth without estrogen. Extracts of freeze...... of the pretherapeutic spectra enabled us to identify the tumor line and the estrogen dependence of the tumors in 80-90% of all cases....

  16. Relevance of estrogenic and aromatase inhibiting effects of mixtures of xenoestrogens for human exposure

    NARCIS (Netherlands)

    van Meeuwen, J.A.

    2008-01-01

    BACKGROUND. Daily humans are exposed to various sources of estrogen-like compounds (xenoestrogens), such as food (naturally occurring, residues or contaminants), clothes and cosmetics. Non-governmental organisations give the impression that this causes adverse effects on human health and the

  17. Phorbol ester induced phosphorylation of the estrogen receptor in intact MCF-7 human breast cancer cells

    International Nuclear Information System (INIS)

    Knabbe, C.; Lippman, M.E.; Greene, G.L.; Dickson, R.B.

    1986-01-01

    Recent studies with a variety of cellular receptors have shown that phorbol ester induced phosphorylation modulates ligand binding and function. In this study the authors present direct evidence that the estrogen receptor in MCF-7 human breast cancer cells is a phosphoprotein whose phosphorylation state can be enhanced specifically by phorbol-12-myristate-13-acetate (PMA). Cells were cultured to 6h in the presence of [ 32 P]-orthophosphate. Whole cell extracts were immunoprecipitated with a monoclonal antibody (D58) against the estrogen receptor and subjected to SDS-polyacrylamide electrophoresis. Autoradiography showed a specific band in the region of 60-62 kDa which was significantly increased in preparations from PMA treated cells. Phospho-amino acid analysis demonstrated specific phosphorylation of serine and threonine residues. Cholera toxin or forskolin did not change the phosphorylation state of this protein. In a parallel binding analysis PMA led to a rapid decrease of estrogen binding sites. The estrogen induction of both progesterone receptors and growth in semisolid medium was blocked by PMA, whereas the estrogen induction of the 8kDa protein corresponding to the ps2 gene product and of the 52 kDa protein was not affected. In conclusion, phorbol esters can induce phosphorylation of the estrogen receptor. This process may be associated with the inactivation of certain receptor functions

  18. Estrogen modification of human glutamate dehydrogenases is linked to enzyme activation state.

    Science.gov (United States)

    Borompokas, Nikolas; Papachatzaki, Maria-Martha; Kanavouras, Konstantinos; Mastorodemos, Vasileios; Zaganas, Ioannis; Spanaki, Cleanthe; Plaitakis, Andreas

    2010-10-08

    Mammalian glutamate dehydrogenase (GDH) is a housekeeping enzyme central to the metabolism of glutamate. Its activity is potently inhibited by GTP (IC(50) = 0.1-0.3 μM) and thought to be controlled by the need of the cell in ATP. Estrogens are also known to inhibit mammalian GDH, but at relatively high concentrations. Because, in addition to this housekeeping human (h) GDH1, humans have acquired via a duplication event an hGDH2 isoform expressed in human cortical astrocytes, we tested here the interaction of estrogens with the two human isoenzymes. The results showed that, under base-line conditions, diethylstilbestrol potently inhibited hGDH2 (IC(50) = 0.08 ± 0.01 μM) and with ∼18-fold lower affinity hGDH1 (IC(50) = 1.67 ± 0.06 μM; p Structure/function analyses revealed that the evolutionary R443S substitution, which confers low basal activity, was largely responsible for sensitivity of hGDH2 to estrogens. Inhibition of both human GDHs by estrogens was inversely related to their state of activation induced by ADP, with the slope of this correlation being steeper for hGDH2 than for hGDH1. Also, the study of hGDH1 and hGDH2 mutants displaying different states of activation revealed that the affinity of estrogen for these enzymes correlated inversely (R = 0.99; p = 0.0001) with basal catalytic activity. Because astrocytes are known to synthesize estrogens, these hormones, by interacting potently with hGDH2 in its closed state, may contribute to regulation of glutamate metabolism in brain.

  19. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

    Science.gov (United States)

    Ren, Chun-E; Zhu, Xueqiong; Li, Jinping; Lyle, Christian; Dowdy, Sean; Podratz, Karl C.; Byck, David; Chen, Hai-Bin; Jiang, Shi-Wen

    2015-01-01

    Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies. PMID:25782154

  20. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

    Directory of Open Access Journals (Sweden)

    Chun-E Ren

    2015-03-01

    Full Text Available Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

  1. Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

    Directory of Open Access Journals (Sweden)

    Venkatachalem Sathish

    2015-06-01

    Full Text Available Aims: Cigarette smoke (CS in active smokers and second-hand smoke exposure exacerbate respiratory disorders such as asthma and chronic bronchitis. While women are known to experience a more asthmatic response to CS than emphysema in men, there is limited information on the mechanisms of CS-induced airway dysfunction. We hypothesize that CS interferes with a normal (protective bronchodilatory role of estrogens, thus worsening airway contractility. Methods: We tested effects of cigarette smoke extract (CSE on 17β-estradiol (E2 signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM obtained from lung samples of non-smoking female patients undergoing thoracic surgery. Results: In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca2+]i responses to 10µM histamine. Acute exposure to physiological concentrations of E2 decreased [Ca2+]i responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E2 on [Ca2+]i was blunted. Acute E2 exposure also decreased store-operated Ca2+ entry and inhibited stromal interaction molecule 1 (STIM1 phosphorylation: effects blunted by CSE. Acute exposure to E2 increased cAMP, but less so in 24h CSE-exposed cells. 24h CSE exposure increased S-nitrosylation of ERα. Furthermore, 24h CSE-exposed bronchial rings showed increased bronchoconstrictor agonist responses that were not reduced as effectively by E2 compared to non-CSE controls. Conclusion: These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.

  2. Environmental estrogens and reproductive health: a discussion of the human and environmental data.

    Science.gov (United States)

    Daston, G P; Gooch, J W; Breslin, W J; Shuey, D L; Nikiforov, A I; Fico, T A; Gorsuch, J W

    1997-01-01

    Estrogenic activity of certain xenobiotics is an established mechanism of toxicity that can impair reproductive function in adults of either sex, lead to irreversible abnormalities when administered during development, or cause cancer. The concern has been raised that exposure to ambient levels of estrogenic xenobiotics may be having widespread adverse effects on reproductive health of humans and wildlife. The purpose of this review is to evaluate (a) the nature of the evidence supporting this concern, and (b) the adequacy of toxicity screening to detect, and risk assessment procedures to establish safe levels for, agents acting by this mechanism. Observations such as adverse developmental effects after maternal exposure to therapeutic levels of the potent estrogen diethylstilbestrol or male fertility problems after exposure to high levels of the weak estrogen chlordecone clearly demonstrate that estrogenicity is active as a toxic mechanism in humans. High level exposures to estrogenic compounds have also been shown to affect specific wildlife populations. However, there is little direct evidence to indicate that exposures to ambient levels of estrogenic xenobiotics are affecting reproductive health. Reports of historical trends showing decreasing reproductive capacity (e.g., decreased sperm production over the last 50 years) are either inconsistent with other data or have significant methodologic inadequacies that hinder interpretation. More reliable historical trend data show an increase in breast cancer rate, but the most comprehensive epidemiology study to data failed to show an association between exposure to persistent, estrogenic organochlorine compounds and breast cancer. Clearly, more work needs to be done to characterize historical trends in humans and background incidence of abnormalities in wildlife populations, and to test hypotheses about ambient exposure to environmental contaminants and toxic effects, before conclusions can be reached about the

  3. Estrogenicity and androgenicity screening of PCB sulfate monoesters in human breast cancer MCF-7 cells.

    Science.gov (United States)

    Flor, Susanne; He, Xianran; Lehmler, Hans-Joachim; Ludewig, Gabriele

    2016-02-01

    Recent studies identified polychlorinated biphenyl (PCB) sulfate esters as a major product of PCB metabolism. Since hydroxy-PCBs (HO-PCBs), the immediate precursors of PCB sulfates and important contributors to PCB toxicity, were shown to have estrogenic activity, we investigated the estrogenicity/androgenicty of a series of PCB sulfate metabolites. We synthesized the five possible structural sulfate monoester metabolites of PCB 3, a congener shown to be biotransformed to sulfates, a sulfate ester of the paint-specific congener PCB 11, and sulfate monoesters of two HO-PCBs reported to interact with sulfotransferases (PCB 39, no ortho chlorines, and PCB 53, 3 ortho chlorines). We tested these PCB sulfates and 4'-HO-PCB 3 as positive control for estrogenic, androgenic, anti-estrogenic, and anti-androgenic activity in the E- and A-screen with human breast cancer MCF7-derived cells at 100 μM-1 pM concentrations. Only 4'-HO-PCB 3 was highly cytotoxic at 100 μM. We observed structure-activity relationships: compounds with a sulfate group in the chlorine-containing ring of PCB 3 (2PCB 3 and 3PCB 3 sulfate) showed no interaction with the estrogen (ER) and androgen (AR) receptor. The 4'-HO-PCB 3 and its sulfate ester had the highest estrogenic effect, but at 100-fold different concentrations, i.e., 1 and 100 μM, respectively. Four of the PCB sulfates were estrogenic (2'PCB 3, 4'PCB 3, 4'PCB 39, and 4'PCB 53 sulfates; at 100 μM). These sulfates and 3'PCB 3 sulfate also exhibited anti-estrogenic activity, but at nM and pM concentrations. The 4'PCB 3 sulfate (para-para' substituted) had the strongest androgenic activity, followed by 3'PCB 3, 4'PCB 53, 4PCB11, and 4PCB 39 sulfates and the 4'HO-PCB 3. In contrast, anti-androgenicity was only observed with the two compounds that have the sulfate group in ortho- or meta- position in the second ring (2'PCB 3 and 3'PCB 3 sulfate). No dose-response was observed in any screen, but, with exception of estrogenic activity (only seen

  4. Estrogen receptor-alpha distribution in the human hypothalamus in relation to sex and endocrine status

    NARCIS (Netherlands)

    Kruijver, Frank P. M.; Balesar, Rawien; Espila, Ana M.; Unmehopa, Unga A.; Swaab, Dick F.

    2002-01-01

    The present study reports the first systematic rostrocaudal distribution of estrogen receptor-a immunoreactivity (ERalpha-ir) in the human hypothalamus and its adjacent areas in young adults. Postmortem material taken from 10 subjects (five male and five female), between 20 and 39 years of age, was

  5. Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

    Science.gov (United States)

    Plasticizers with estrogenic activity, such as bisphenol A (BPA), have potential adverse health effects in humans. Due to mounting evidence of these health effects, BPA is being phased out and replaced by other bisphenol variants in “BPA-free” products. We have compared estrogeni...

  6. Estrogenic Activity of Coumestrol, DDT, and TCDD in Human Cervical Cancer Cells

    Directory of Open Access Journals (Sweden)

    Kenneth Ndebele

    2010-05-01

    Full Text Available Endogenous estrogens have dramatic and differential effects on classical endocrine organ and proliferation. Xenoestrogens are environmental estrogens that have endocrine impact, acting as both estrogen agonists and antagonists, but whose effects are not well characterized. In this investigation we sought to delineate effects of xenoestrogens. Using human cervical cancer cells (HeLa cells as a model, the effects of representative xenoestrogens (Coumestrol-a phytoestrogen, tetrachlorodioxin (TCDD-a herbicide and DDT-a pesticide on proliferation, cell cycle, and apoptosis were examined. These xenoestrogens and estrogen inhibited the proliferation of Hela cells in a dose dependent manner from 20 to 120 nM suggesting, that 17-β-estrtadiol and xenoestrogens induced cytotoxic effects. Coumestrol produced accumulation of HeLa cells in G2/M phase, and subsequently induced apoptosis. Similar effects were observed in estrogen treated cells. These changes were associated with suppressed bcl-2 protein and augmented Cyclins A and D proteins. DDT and TCDD exposure did not induce apoptosis. These preliminary data taken together, suggest that xenoestrogens have direct, compound-specific effects on HeLa cells. This study further enhances our understanding of environmental modulation of cervical cancer.

  7. Urinary estrogen excretion and concentration of serum human placental lactogen in pregnancies following legally induced abortion

    DEFF Research Database (Denmark)

    Obel, E B; Madsen, Mette

    1980-01-01

    Feto-placental function was assessed by 24-hour excretion of estrogen in urine and by the concentration of human Placental Lactogen (hPL) in serum in pregnant women whose previous pregnancy was terminated by legally induced abortion. The mean 24-hour excretion of estrogens in urine and the mean...... an increased frequency of dysfunction of the feto-placental unit during the last part of pregnancy in women with previous legally induced abortion. These findings indicate that legal abortion does not seem to increase the frequency of retarded intrauterine growth in a subsequent pregnancy....... concentration of hPL in serum were no lower in this group than in women without previous induced abortion. Neither was the frequency of a low 24-hour excretion of estrogens in urine or low concentration of hPL in serum (values less than mean - 1.96 s) found to be increased. This study could not demonstrate...

  8. Influence of estrogenic pesticides on membrane integrity and membrane transfer of monosaccharide into the human red cell

    International Nuclear Information System (INIS)

    Ingermann, R.L.

    1989-01-01

    Some natural and synthetic estrogens inhibit carrier-mediated transport of glucose into human red blood cells and membrane vesicles from the placenta. The inhibitory action of these estrogens on transport appears to be a direct effect at the membrane and does not involve receptor binding and protein synthesis. It is not clear, however, whether such inhibition is a common feature among estrogenic agents. Several chlorinated hydrocarbon pesticides have been shown to possess estrogenic activity. These pesticides could have inhibitory effects on the human sodium-independent glucose transporter. Owing to the apparent importance of this membrane transporter in human tissues, direct interaction of hormones and xenobiotics with the glucose transporter is of fundamental significance. Some pesticides have been shown to alter membrane structure directly and alter the passive permeability of membranes. Whether the estrogenic pesticides influence passive diffusion of sugars across membranes has not been established. Finally, preliminary observations have suggested that some estrogens and pesticides have lytic effects on intact cells. Consequently, this study focuses on the ability of several estrogens and estrogenic pesticides to disrupt the cell membrane, influence the monosaccharide transporter, and alter the rate of monosaccharide permeation through the membrane by simple diffusion

  9. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines.

    Science.gov (United States)

    Lam, Siew Hong; Lee, Serene G P; Lin, Chin Y; Thomsen, Jane S; Fu, Pan Y; Murthy, Karuturi R K; Li, Haixia; Govindarajan, Kunde R; Nick, Lin C H; Bourque, Guillaume; Gong, Zhiyuan; Lufkin, Thomas; Liu, Edison T; Mathavan, Sinnakaruppan

    2011-05-16

    The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa). Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE), is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry points for estrogen regulation. The findings

  10. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

    Directory of Open Access Journals (Sweden)

    Govindarajan Kunde R

    2011-05-01

    Full Text Available Abstract Background The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Methods Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen and an anti-estrogen (ICI 182,780. Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa. Results Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE, is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry

  11. Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors

    Directory of Open Access Journals (Sweden)

    Thomas L. Shaak

    2013-01-01

    Full Text Available DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects.

  12. The emerging role of estrogen receptor-β in human reproduction.

    Science.gov (United States)

    Su, Emily J; Xin, Hong; Monsivais, Diana

    2012-01-01

    Knowledge surrounding estrogen and estrogen receptor biology continues to evolve, and the diversity of their actions and complexity of their mechanisms are becoming increasingly evident. Estrogen receptor (ER) regulation of reproduction is no exception. Although it is well established that estrogen and ERα play key roles in mediating several reproductive biological processes, such as myometrial and endometrial growth, increasing evidence suggests that ERβ is also an important factor. ERβ is a key mediator in folliculogenesis and may also play a role in stimulating ovulation and regulating aspects of luteinization. ERβ is also expressed in higher quantities than ERα in the human myometrium and cervix during pregnancy, and thus it may play a part in the initiation of labor and parturition. Finally, ERβ is the sole ER expressed within the endothelium of the endometrium and the fetoplacental vasculature, and studies suggest that its role may contribute to angiogenic and vasomotor changes that play a role in both implantation and regulation of fetoplacental blood flow. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  13. Impact of estrogenic compounds on DNA integrity in human spermatozoa: Evidence for cross-linking and redox cycling activities

    Energy Technology Data Exchange (ETDEWEB)

    Bennetts, L.E.; De Iuliis, G.N.; Nixon, B.; Kime, M.; Zelski, K. [ARC Centre of Excellence in Biotechnology and Development and Discipline of Biological Sciences, University of Newcastle, NSW (Australia); McVicar, C.M.; Lewis, S.E. [Obstetrics and Gynaecology, Queen' s University, Belfast (United Kingdom); Aitken, R.J. [ARC Centre of Excellence in Biotechnology and Development and Discipline of Biological Sciences, University of Newcastle, NSW (Australia)], E-mail: jaitken@mail.newcastle.edu.au

    2008-05-10

    A great deal of circumstantial evidence has linked DNA damage in human spermatozoa with adverse reproductive outcomes including reduced fertility and high rates of miscarriage. Although oxidative stress is thought to make a significant contribution to DNA damage in the male germ line, the factors responsible for creating this stress have not been elucidated. One group of compounds that are thought to be active in this context are the estrogens, either generated as a result of the endogenous metabolism of androgens within the male reproductive tract or gaining access to the latter as a consequence of environmental exposure. In this study, a wide variety of estrogenic compounds were assessed for their direct effects on human spermatozoa in vitro. DNA integrity was assessed using the Comet and TUNEL assays, lesion frequencies were quantified by QPCR using targets within the mitochondrial and nuclear ({beta}-globin) genomes, DNA adducts were characterized by mass spectrometry and redox activity was monitored using dihydroethidium (DHE) as the probe. Of the estrogenic and estrogen analogue compounds evaluated, catechol estrogens, quercetin, diethylstilbestrol and pyrocatechol stimulated intense redox activity while genistein was only active at the highest doses tested. Other estrogens and estrogen analogues, such as 17{beta}-estradiol, nonylphenol, bisphenol A and 2,3-dihydroxynaphthalene were inactive. Estrogen-induced redox activity was associated with a dramatic loss of motility and, in the case of 2-hydroxyestradiol, the induction of significant DNA fragmentation. Mass spectrometry also indicated that catechol estrogens were capable of forming dimers that can cross-link the densely packed DNA strands in sperm chromatin, impairing nuclear decondensation. These results highlight the potential importance of estrogenic compounds in creating oxidative stress and DNA damage in the male germ line and suggest that further exploration of these compounds in the aetiology of

  14. Estrogenic endocrine disruptors present in sports supplements. A risk assessment for human health.

    Science.gov (United States)

    Plotan, Monika; Elliott, Christopher T; Frizzell, Caroline; Connolly, Lisa

    2014-09-15

    Sports supplements are becoming a regular dietary addition for consumers who view such products as a means of improving their health and performance. Previously estrogenic endocrine disruptors (EDs) were detected in 80% of 116 sports supplements investigated by biological in vitro reporter gene assays (RGAs). The aim of this study was to quantify the hormonal activity in 50 of these sports supplement samples using a validated estrogen RGA and perform an exposure and risk assessment for human health. Results showed that 17β-estradiol equivalent levels were higher than those reported as being present in the typical human omnivore diet in 33 of the sports supplements and higher than the acceptable daily intake (ADI) in 13 of these products. The highest activity samples presented a potential to influence the human daily exposure to 17β-estradiol like activity in various risk groups with a predicted hormonal impact of greatest concern in young boys and postmenopausal women. In conclusion, consumers of sports supplements may be exposed to high levels of estrogenic EDs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Estrogen regulates progesterone production by human placental trophoblast cells in culture

    International Nuclear Information System (INIS)

    Grimes, R.W.

    1990-01-01

    We have suggested that estrogen regulates placental low-density lipoprotein (LDL) uptake and thus progesterone (P 4 ) production during primate pregnancy based on results obtained in antiestrogen-treated baboons. The objectives of the present study, were to determine whether estrogen is also important to regulation of P 4 formation by the human placenta, and whether effects of estrogen were mediated by availability of cholesterol substrate via the LDL, de novo, or deesterification pathways. Term human placenta were dispersed in 0.125% trypsin, cytotrophoblasts were purified via a 70-5% Percoll gradient, incubated 72 h in DMEM with 10% FBS to stimulate formation of syncytia, then incubated an additional 48 h with estradiol (E2). In Experiment 1, 1 μg/ml E 2 and 500 μg/MI LDL-protein, stimulated P 4 (P 2 increased LDL uptake. Scatchard analysis indicated that trophoblast uptake of [ 125 I]LDL (ng/mg cell protein) was 50% greater (P 2 (mean ± SE, 638 +/- 23; n = 6) than DMEM in the presence of antiestrogen MER-25. Moreover, uptake and degradation of LDL, and cellular content of free and esterified cholesterol, increased in a dose-dependent manner with 0.1 to 1000 ng/ml E 2 . These results suggest that estrogen regulates placental cell uptake of LDL and thus availability of cholesterol for P 4 biosynthesis during human pregnancy. In Experiment 2, E 2 Stimulated P 4 formation (ng/mg cell protein/48 h) from a control level of 194 ± 25 to 357 ± 62, in the absence of LDL. Under these conditions, cholesterol for P 4 biosynthesis must have been derived from de novo synthesis and/or deesterification of cholesteryl ester stores

  16. Preliminary genetic imaging study of the association between estrogen receptor-α gene polymorphisms and harsh human maternal parenting.

    Science.gov (United States)

    Lahey, Benjamin B; Michalska, Kalina J; Liu, Chunyu; Chen, Qi; Hipwell, Alison E; Chronis-Tuscano, Andrea; Waldman, Irwin D; Decety, Jean

    2012-09-06

    A failure of neural changes initiated by the estrogen surge in late pregnancy to reverse the valence of infant stimuli from aversive to rewarding is associated with dysfunctional maternal behavior in nonhuman mammals. Estrogen receptor-α plays the crucial role in mediating these neural effects of estrogen priming. This preliminary study examines associations between estrogen receptor-α gene polymorphisms and human maternal behavior. Two polymorphisms were associated with human negative maternal parenting. Furthermore, hemodynamic responses in functional magnetic resonance imaging to child stimuli in neural regions associated with social cognition fully mediated the association between genetic variation and negative parenting. This suggests testable hypotheses regarding a biological pathway between genetic variants and dysfunctional human maternal parenting. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: evidence for an estrogen surface receptor.

    Science.gov (United States)

    Stefano, G B; Prevot, V; Beauvillain, J C; Fimiani, C; Welters, I; Cadet, P; Breton, C; Pestel, J; Salzet, M; Bilfinger, T V

    1999-10-01

    We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase (cNOS) activity in human peripheral monocytes by acting on an estrogen surface receptor. NO release was measured in real time with an amperometric probe. 17beta-estradiol exposure to monocytes stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol had no effect. 17beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA, whereas ICI 182,780, a selective inhibitor of the nuclear estrogen receptor, had no effect. We further showed, using a dual emission microfluorometry in a calcium-free medium, that the 17beta-estradiol-stimulated release of monocyte NO was dependent on the initial stimulation of intracellular calcium transients in a tamoxifen-sensitive process. Leeching out the intracellular calcium stores abolished the effect of 17beta-estradiol on NO release. RT-PCR analysis of RNA obtained from the cells revealed a strong estrogen receptor-alpha amplification signal and a weak beta signal. Taken together, a physiological dose of estrogen acutely stimulates NO release from human monocytes via the activation of an estrogen surface receptor that is coupled to increases in intracellular calcium.

  18. Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Yardley DA

    2016-05-01

    Full Text Available Denise A Yardley1,2 1Sarah Cannon Research Institute, Nashville, TN, USA; 2Tennessee Oncology, Nashville, TN, USA Abstract: There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current understanding of molecular and biological mechanisms involved in bone turnover and metastases, increased risk for bone-related complications from breast cancer and breast cancer therapy, and current and emerging treatment strategies for managing bone metastases and bone turnover in postmenopausal women with hormone receptor-positive breast cancer. Keywords: breast cancer, bone metastases, hormone receptor-positive, bone-related complications, interventions, management and management strategies, estrogen receptor-positive

  19. Membrane Estrogen and HER-2 Receptors in Human Breast Cancer

    Science.gov (United States)

    2002-07-01

    1986). Expression of the epider- mal growth factor receptors on human cervical , ovarian and vulvar carcinomas. Cancer Res.,46: 285-293. 9.) Coussens...neurone signaling; immune and inflammatory reactions; apoptosis Aldosterone Promotion of reabsorption of sodium and excretion of potassium in kidney

  20. A Case of Disease Improvement after Treatment with Everolimus plus Exemestane in a Patient with Hormone Receptor-Positive Metastatic Breast Cancer with Bone Metastases

    Directory of Open Access Journals (Sweden)

    J. Thaddeus Beck

    2015-02-01

    Full Text Available Breast cancer is one of the most frequently diagnosed cancers and a leading cause of death in women worldwide. Despite significant advances in the treatment of hormone receptor-positive breast cancer, tumor metastasis occurs frequently and is associated with poor long-term prognosis. The mammalian target of rapamycin (mTOR pathway plays a central role in cancer cell growth, proliferation, and resistance to endocrine therapies. Therefore, mTOR inhibitors such as everolimus in combination with nonsteroidal aromatase inhibitors might reverse endocrine resistance and improve clinical outcomes in patients. Here, we report on a case of infiltrating lobular carcinoma of the breast with metastases to the bone. Histopathologic analysis showed that the patient was estrogen and progesterone receptor positive and human epidermal growth factor-2 negative. This case represents the clinical spectrum of complications caused by metastasis: the patient experienced a considerable amount of skeletal-related complications, had previously received chemotherapy, and experienced disease progression while taking nonsteroidal aromatase inhibitors. After treatment with oral everolimus 10 mg daily plus oral exemestane 25 mg daily, the patient's disease was ameliorated. Combination therapy was well tolerated, with minimal adverse effects that were manageable with concomitant medications. Although further analyses in larger populations are necessary, the addition of everolimus to exemestane might provide an effective new treatment option for patients with bone metastasis.

  1. Gene expression changes induced by estrogen and selective estrogen receptor modulators in primary-cultured human endometrial cells: signals that distinguish the human carcinogen tamoxifen

    International Nuclear Information System (INIS)

    Pole, Jessica C.M.; Gold, Leslie I.; Orton, Terry; Huby, Russell; Carmichael, Paul L.

    2005-01-01

    Tamoxifen has long been the endocrine treatment of choice for women with breast cancer and is now employed for prophylactic use in women at high risk from breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, mimic some of tamoxifen's beneficial effects and, like tamoxifen, exhibit a complex mixture of organ-specific estrogen agonist and antagonistic properties. However, accompanying the positive effects of tamoxifen has been the emergence of evidence for an increased risk of endometrial cancer associated with its use. A more complete understanding of the mechanism(s) of SERM carcinogenicity and endometrial effects is therefore required. We have sought to compare and characterise the transcript profile of tamoxifen, raloxifene and the agonist estradiol in human endometrial cells. Using primary cultures of human endometria, to best emulate the in vivo responses in a manageable in vitro system, we have shown 230 significant changes in gene expression for epithelial cultures and 83 in stromal cultures, either specific to 17β-estradiol, tamoxifen or raloxifene, or changed across more than one of the treatments. Considering the transcriptome as a whole, the endometrial responses to raloxifene or tamoxifen were more similar than either drug was to 17β-estradiol. Treatment of endometrial cultures with tamoxifen resulted in the largest number of gene changes relative to control cultures and a high proportion of genes associated with regulation of gene transcription, cell-cycle control and signal transduction. Tamoxifen-specific changes that might point towards mechanisms for its proliferative response in the endometrium included changes in retinoblastoma and c-myc binding proteins, the APCL, dihydrofolate reductase (DHFR) and E2F1 genes and other transcription factors. Tamoxifen was also found to give rise to the highest number of gene expression changes common to those that characterise malignant endometria. It is anticipated that this

  2. Triclosan causes spontaneous abortion accompanied by decline of estrogen sulfotransferase activity in humans and mice.

    Science.gov (United States)

    Wang, Xiaoli; Chen, Xiaojiao; Feng, Xuejiao; Chang, Fei; Chen, Minjian; Xia, Yankai; Chen, Ling

    2015-12-15

    Triclosan (TCS), an antibacterial agent, is identified in serum and urine of humans. Here, we show that the level of urinary TCS in 28.3% patients who had spontaneous abortion in mid-gestation were increased by 11.3-fold (high-TCS) compared with normal pregnancies. Oral administration of TCS (10 mg/kg/day) in mice (TCS mice) caused an equivalent urinary TCS level as those in the high-TCS abortion patients. The TCS-exposure from gestation day (GD) 5.5 caused dose-dependently fetal death during GD12.5-16.5 with decline of live fetal weight. GD15.5 TCS mice appeared placental thrombus and tissue necrosis with enhancement of platelet aggregation. The levels of placenta and plasma estrogen sulfotransferase (EST) mRNA and protein in TCS mice or high-TCS abortion patients were not altered, but their EST activities were significantly reduced compared to controls. Although the levels of serum estrogen (E2) in TCS mice and high-TCS abortion patients had no difference from controls, their ratio of sulfo-conjugated E2 and unconjugated E2 was reduced. The estrogen receptor antagonist ICI-182,780 prevented the enhanced platelet aggregation and placental thrombosis and attenuated the fetal death in TCS mice. The findings indicate that TCS-exposure might cause spontaneous abortion probably through inhibition of EST activity to produce placental thrombosis.

  3. Human Umbilical Cord Blood Cells or Estrogen may be Beneficial in Treating Heatstroke

    Directory of Open Access Journals (Sweden)

    Sheng-Hsien Chen

    2007-03-01

    Full Text Available This current review summarized animal models of heatstroke experimentation that promote our current knowledge of therapeutic effects on cerebrovascular dysfunction, coagulopathy, and/or systemic inflammation with human umbilical cord blood cells (HUCBCs or estrogen in the setting of heatstroke. Accumulating evidences have demonstrated that HUCBCs provide a promising new therapeutic method against neurodegenerative diseases, such as stroke, traumatic brain injury, and spinal cord injury as well as blood disease. More recently, we have also demonstrated that postor pretreatment by HUCBCs may resuscitate heatstroke rats with by reducing circulatory shock, and cerebral nitric oxide overload and ischemic injury. Moreover, CD34+ cells sorted from HUCBCs may improve survival by attenuating inflammatory, coagulopathy, and multiorgan dysfunction during experimental heatstroke. Many researchers indicated pro(e.g. tumor necrosis factor-α [TNF-α] and anti-inflammatory (e.g. interleukin-10 [IL-10] cytokines in the peripheral blood stream correlate with severity of circulatory shock, cerebral ischemia and hypoxia, and neuronal damage occurring in heatstroke. It has been shown that intravenous administration of CD34+ cells can secrete therapeutic molecules, such as neurotrophic factors, and attenuate systemic inflammatory reactions by decreasing serum TNF-α but increasing IL-10 during heatstroke. Another line of evidence has suggested that estrogen influences the severity of injury associated with cerebrovascular shock. Recently, we also successfully demonstrated estrogen resuscitated heatstroke rats by ameliorating systemic inflammation. Conclusively, HUCBCs or estrogen may be employed as a beneficial therapeutic strategy in prevention and repair of cerebrovascular dysfunction, coagulopathy, and/or systemic inflammation during heatstroke.

  4. Regulation of human CYP27A1 by estrogens and androgens in HepG2 and prostate cells.

    Science.gov (United States)

    Tang, Wanjin; Norlin, Maria; Wikvall, Kjell

    2007-06-01

    The regulation of the human CYP27A1 gene by estrogens and androgens was studied in human liver-derived HepG2 and prostate cells. Our results show that the promoter activity, enzymatic activity and mRNA levels of CYP27A1 in HepG2 cells are downregulated by estrogen in presence of ERalpha or ERbeta. Similar effects by estrogen were found in RWPE-1 prostate cells. In contrast, estrogen markedly upregulated the transcriptional activity of CYP27A1 in LNCaP prostate cancer cells. 5alpha-Dihydrotestosterone and androgen receptor upregulated the transcriptional activity of CYP27A1 in HepG2 cells. Progressive deletion experiments indicate that the ERbeta-mediated effects in HepG2 and LNCaP cells are conferred to the same region (-451/+42) whereas ERalpha-mediated effects on this promoter are more complex. The results indicate that the stimulating effect of androgen in HepG2 cells is conferred to a region upstream from -792 in the CYP27A1 promoter. In summary, we have identified the human CYP27A1 gene as a target for estrogens and androgens. The results imply that expression of CYP27A1 may be affected by endogenous sex hormones and pharmacological compounds with estrogenic or androgenic effects.

  5. Cholesterol synthesis inhibitor RO 48-8071 suppresses transcriptional activity of human estrogen and androgen receptor.

    Science.gov (United States)

    Mafuvadze, Benford; Liang, Yayun; Hyder, Salman M

    2014-10-01

    Breast cancer cells express enzymes that convert cholesterol, the synthetic precursor of steroid hormones, into estrogens and androgens, which then drive breast cancer cell proliferation. In the present study, we sought to determine whether oxidosqualene cyclase (OSC), an enzyme in the cholesterol biosynthetic pathway, may be targeted to suppress progression of breast cancer cells. In previous studies, we showed that the OSC inhibitor RO 48-8071 (RO) may be a ligand which could potentially be used to control the progression of estrogen receptor-α (ERα)-positive breast cancer cells. Herein, we showed, by real-time PCR analysis of mRNA from human breast cancer biopsies, no significant differences in OSC expression at various stages of disease, or between tumor and normal mammary cells. Since the growth of hormone-responsive tumors is ERα-dependent, we conducted experiments to determine whether RO affects ERα. Using mammalian cells engineered to express human ERα or ERβ protein, together with an ER-responsive luciferase promoter, we found that RO dose-dependently inhibited 17β-estradiol (E2)-induced ERα responsive luciferase activity (IC50 value, ~10 µM), under conditions that were non-toxic to the cells. RO was less effective against ERβ-induced luciferase activity. Androgen receptor (AR) mediated transcriptional activity was also reduced by RO. Notably, while ERα activity was reduced by atorvastatin, the HMG-CoA reductase inhibitor did not influence AR activity, showing that RO possesses broader antitumor properties. Treatment of human BT-474 breast cancer cells with RO reduced levels of estrogen-induced PR protein, confirming that RO blocks ERα activity in tumor cells. Our findings demonstrate that an important means by which RO suppresses hormone-dependent growth of breast cancer cells is through its ability to arrest the biological activity of ERα. This warrants further investigation of RO as a potential therapeutic agent for use against hormone

  6. Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue

    International Nuclear Information System (INIS)

    Wang, Li-Shu; Huang, Yi-Wen; Liu, Suling; Yan, Pearlly; Lin, Young C

    2008-01-01

    Conjugated linoleic acid (CLA), a naturally occurring fatty acid found in ruminant products such as milk and beef, has been shown to possess anti-cancer activities in in vivo animal models and in vitro cell culture systems. In human breast cancer, the overall duration of estrogen exposure is the most important risk factor for developing estrogen-responsive breast cancer. Accordingly, it has been suggested that estrogen exposure reduces apoptosis through the up-regulation of the anti-apoptosis protein, Bcl-2. Bcl-2, an anti-apoptotic protein, regulates apoptosis and plays a crucial role in the development and growth regulation of normal and cancerous cells. Our research interest is to examine the effects of CLA on the induction of apoptosis in human breast tissues. The localization of Bcl-2 in both normal and cancerous human breast tissues was determined by immunohistochemical staining and the Bcl-2 protein expression was tested by western blot analysis. Co-culture of epithelial cells and stromal cells was carried out in the presence or absence of CLA to evaluate apoptosis in the context of a cell-cell interaction. The results showed that both normal and cancerous breast tissues were positive for Bcl-2 staining, which was higher overall in mammary ducts but very low in the surrounding stromal compartment. Interestingly, by quantifying the western blot data, basal Bcl-2 protein levels were higher in normal breast epithelial cells than in cancerous epithelial cells. Furthermore, treatment with 17β-estradiol (E 2 ) stimulated growth and up-regulated Bcl-2 expression in estrogen responsive breast epithelial cells; however, these carcinogenic effects were diminished by either CLA or 4-Hydroxytamoxifen (Tam) and were suppressed further by the combination of CLA and Tam. In both one cell type cultured and co-culture systems, CLA induced cell apoptosis in ERα transfected MDA-MB-231 cells but not in the wild type MDA-MB-231 cells. These data, therefore, demonstrate that

  7. Estrogens and development

    Energy Technology Data Exchange (ETDEWEB)

    McLachlan, J.A.; Newbold, R.R.

    1987-11-01

    The normal development of the genital organs of mammals, including humans, is under hormonal control. A role for the female sex hormone estrogen in this process is still unclear. However, exposure of experimental animals or humans to the potent exogenous estrogen, diethylstilbestrol (DES), results in persistent differentiation effects. Since many chemicals in the environment are weakly estrogenic, the possibility of hormonally altered differentiation must be considered.

  8. Roles of ERβ and GPR30 in Proliferative Response of Human Bladder Cancer Cell to Estrogen

    Directory of Open Access Journals (Sweden)

    Weiren Huang

    2015-01-01

    Full Text Available Bladder cancer belongs to one of the most common cancers and is a leading cause of deaths in our society. Urothelial carcinoma of the bladder (UCB is the main type of this cancer, and the estrogen receptors in UCB remain to be studied. Our experiment aimed to investigate the possible biological effect of 17β-estradiol on human bladder-derived T24 carcinoma cells and to indicate its related mechanisms. T24 cells were treated with various doses of 17β-estradiol, and cell proliferation was detected using MTT assays. 17β-estradiol promoted T24 cell proliferation independent of ERβ/GPR30-regulated EGFR-MAPK pathway, while it inhibited cell growth via GPR30. Furthermore, the expression levels of downstream genes (c-FOS, BCL-2, and CYCLIN D1 were increased by 17β-estradiol and this effect was independently associated with activity of the EGFR-MAPK pathway. The two estrogen receptors might be potential therapeutic targets for the treatment of bladder cancer.

  9. Positron emission mammography: correlation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status and 18F-FDG.

    Science.gov (United States)

    Wang, Carolyn L; MacDonald, Lawrence R; Rogers, James V; Aravkin, Aleksandr; Haseley, David R; Beatty, J David

    2011-08-01

    The study objective was to assess the correlation between (18)F-FDG uptake values on positron emission mammography (PEM), expressed as maximum uptake value and lesion-to-background ratio, and receptor status (i.e., estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]), tumor histology, and tumor grade. We also evaluated for the correlation between maximum uptake value on PEM and maximum uptake value on a whole-body PET/CT. We retrospectively reviewed our database for patients with newly diagnosed breast cancer who were referred for PEM between June 2007 and September 2009. A subset of patients also underwent a whole-body PET/CT scan. The original pathology reports were reviewed to establish the histologic type, grade, and receptor status. The study involved 98 patients with 100 lesions. ER-negative tumors and PR-negative tumors had significantly higher mean lesion-to-background ratio than did their respective receptor-positive tumors (p = 0.02). Triple-negative tumors (i.e., ER-negative, PR-negative, and HER2-negative tumors) had statistically higher mean lesion-to-background ratio than did ER-positive PR-positive HER2-negative tumors (p = 0.04). Infiltrating ductal carcinomas had significantly higher PEM FDG uptake values than did infiltrating lobular carcinomas (p = 0.02-0.04). Breast tumors with higher histologic grade also had significantly higher PEM FDG uptake values than did those with lower grade (p = 0.03 and p PEM uptake values. This study shows a correlation between PEM FDG uptake values and the prognostic factors that have been shown to predict breast cancer survival.

  10. Estrogen receptor beta-selective agonists stimulate calcium oscillations in human and mouse embryonic stem cell-derived neurons.

    Directory of Open Access Journals (Sweden)

    Lili Zhang

    2010-07-01

    Full Text Available Estrogens are used extensively to treat hot flashes in menopausal women. Some of the beneficial effects of estrogens in hormone therapy on the brain might be due to nongenomic effects in neurons such as the rapid stimulation of calcium oscillations. Most studies have examined the nongenomic effects of estrogen receptors (ER in primary neurons or brain slices from the rodent brain. However, these cells can not be maintained continuously in culture because neurons are post-mitotic. Neurons derived from embryonic stem cells could be a potential continuous, cell-based model to study nongenomic actions of estrogens in neurons if they are responsive to estrogens after differentiation. In this study ER-subtype specific estrogens were used to examine the role of ERalpha and ERbeta on calcium oscillations in neurons derived from human (hES and mouse embryonic stem cells. Unlike the undifferentiated hES cells the differentiated cells expressed neuronal markers, ERbeta, but not ERalpha. The non-selective ER agonist 17beta-estradiol (E(2 rapidly increased [Ca2+]i oscillations and synchronizations within a few minutes. No change in calcium oscillations was observed with the selective ERalpha agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyltrisphenol (PPT. In contrast, the selective ERbeta agonists, 2,3-bis(4-Hydroxyphenyl-propionitrile (DPN, MF101, and 2-(3-fluoro-4-hydroxyphenyl-7-vinyl-1,3 benzoxazol-5-ol (ERB-041; WAY-202041 stimulated calcium oscillations similar to E(2. The ERbeta agonists also increased calcium oscillations and phosphorylated PKC, AKT and ERK1/2 in neurons derived from mouse ES cells, which was inhibited by nifedipine demonstrating that ERbeta activates L-type voltage gated calcium channels to regulate neuronal activity. Our results demonstrate that ERbeta signaling regulates nongenomic pathways in neurons derived from ES cells, and suggest that these cells might be useful to study the nongenomic mechanisms of estrogenic compounds.

  11. In vitro study on effect of germinated wheat on human breast cancer cells

    Science.gov (United States)

    This research investigated the possible anti-cancer effects of germinated wheat flours (GWF) on cell growth and apoptosis of human breast cancer cells. In a series of in vitro experiments, estrogen receptor-positive (MCF-7) and negative (MDA-MB-231) cells were cultured and treated with GWF that wer...

  12. Effect of in vitro estrogenic pesticides on human oestrogen receptor α and β mRNA levels

    DEFF Research Database (Denmark)

    Theander Grünfeld, Heidi; Bonefeld-Jørgensen, Eva Cecilie

    2004-01-01

    Nine widely distributed pesticides were recently demonstrated to posses potential estrogenic properties in oestrogen receptor (ER) transactivation and/or E-screen assays. We tested the effect of these nine pesticides on the human ERα and ERβ mRNA steady state levels in the mamma cancer fibroblast...

  13. MOLECULAR DOCKING OF COMPOUNDS FROM Chaetomium Sp. AGAINST HUMAN ESTROGEN RECEPTOR ALPHA IN SEARCHING ANTI BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Maywan Hariono

    2016-05-01

    Full Text Available A study on molecular docking-based virtual screening has been conducted to select virtual hit of compounds, reported its existence in fungal endophytes of Chaetomium sp. as cytotoxic agent of breast cancer. The ligands were docked into Human Estrogen Receptor alpha (HERa as the protein which regulates the breast cancer growth via estradiol-estrogen receptor binding intervention. The results showed that two compounds bearing xanthone and two compounds bearing benzonaphtyridinedione scaffolds were selected as virtual hit ligands for HERa leading to the conclusion that these compounds were good to be developed as anti breast cancer.

  14. Estrogen receptors in the human male bladder, prostatic urethra, and prostate. An immunohistochemical and biochemical study

    DEFF Research Database (Denmark)

    Bødker, A; Balslev, E; Juul, B R

    1995-01-01

    The distribution and quantity of estrogen receptors (ERs) in the human male bladder, prostatic urethra and the prostate were studied in eight males with recurrent papillomas of the bladder or monosymptomatic hematuria (median age 61 years), 14 men undergoing transurethral resection due to benign...... prostatic hyperplasia (median age 70 years), and nine men undergoing cystectomy due to malignant tumour of the bladder (median age 70 years). In the first group of patients, biopsies for immunohistochemical examination were obtained from the bladder vault, bottom, both side-walls, the trigone area......, and the mid-portion of the prostatic urethra, and in the second group from three locations of the prostatic urethra (bladder neck, mid-portion and veramontanum). In the third group, tissue specimens were taken from the vault of the bladder, prostatic urethra, and the prostate, for immunohistochemical as well...

  15. Utilizing induced pluripotent stem cells (iPSCs) to understand the actions of estrogens in human neurons.

    Science.gov (United States)

    Shum, Carole; Macedo, Sara C; Warre-Cornish, Katherine; Cocks, Graham; Price, Jack; Srivastava, Deepak P

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". Over recent years tremendous progress has been made towards understanding the molecular and cellular mechanism by which estrogens exert enhancing effects on cognition, and how they act as a neuroprotective or neurotrophic agent in disease. Currently, much of this work has been carried out in animal models with only a limited number of studies using native human tissue or cells. Recent advances in stem cell technology now make it possible to reprogram somatic cells from humans into induced pluripotent stem cells (iPSCs), which can subsequently be differentiated into neurons of specific lineages. Importantly, the reprogramming of cells allows for the generation of iPSCs that retain the genetic "makeup" of the donor. Therefore, it is possible to generate iPSC-derived neurons from patients diagnosed with specific diseases, that harbor the complex genetic background associated with the disorder. Here, we review the iPSC technology and how it's currently being used to model neural development and neurological diseases. Furthermore, we explore whether this cellular system could be used to understand the role of estrogens in human neurons, and present preliminary data in support of this. We further suggest that the use of iPSC technology offers a novel system to not only further understand estrogens' effects in human cells, but also to investigate the mechanism by which estrogens are beneficial in disease. Developing a greater understanding of these mechanisms in native human cells will also aid in the development of safer and more effective estrogen-based therapeutics. Copyright © 2015. Published by Elsevier Inc.

  16. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    International Nuclear Information System (INIS)

    Prouillac, Caroline; Koraichi, Farah; Videmann, Bernadette; Mazallon, Michelle; Rodriguez, Frédéric; Baltas, Michel; Lecoeur, Sylvaine

    2012-01-01

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.

  17. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    Energy Technology Data Exchange (ETDEWEB)

    Prouillac, Caroline, E-mail: c.prouillac@vetagro-sup.fr [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France); Koraichi, Farah; Videmann, Bernadette; Mazallon, Michelle [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France); Rodriguez, Frédéric; Baltas, Michel [Université Paul Sabatier, SPCMIB-UMR5068, Laboratoire de Synthèse et de Physicochimie des Molécules d' Intérêt Biologique, 118 route de Narbonne, 31062 TOULOUSE cedex 9 (France); Lecoeur, Sylvaine [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l' Etoile (France)

    2012-03-15

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.

  18. A Brief Account of the Discovery of the Fetal/Placental Unit for Estrogen Production in Equine and Human Pregnancies: Relation to Human Medicine.

    Science.gov (United States)

    Raeside, James I

    2017-09-01

    The role of steroids in human medicine is well recognized, but the major contributions made by the large domestic animals as a source of material in the discovery, isolation, and determination of the structure of the steroid hormones is less well appreciated. After a brief reminder of the early efforts to obtain a reliable source of steroids for clinical use, the narrative here is to outline one example where success was ultimately achieved for estrogen replacement therapy. Whereas knowledge of the high concentrations of estrogens in urine of pregnant women and mares dates from the late 1920s, it was not until the 1940s that the latter was shown to be a practical source. Initially, the placenta was held to be responsible, but the involvement of the fetus in each case was eventually established. The remarkable enlargement of the human fetal adrenal glands and the fetal gonads in the horse, with characteristic features of steroid secreting tissues, suggested their participation. Ultimately, it was 16-hydroxylation by the fetal liver that resulted in estriol being the major estrogen type, by far, in late human pregnancy. In the mare, the pattern of estrogen production reflected that of the growth and later regression of the fetal gonads. The characteristic production ring-B, unsaturated estrogens in the mare is derived from an alternative pathway involving retention of the additional double bond in the biosynthesis of equilin.

  19. Estrogen stimulates adenosine receptor expression subtypes in human breast cancer MCF-7 cell line.

    Science.gov (United States)

    Mohamadi, Azam; Aghaei, Mahmoud; Panjehpour, Mojtaba

    2018-02-01

    Estrogen is a steroid hormone that plays a key role in the development and regulation of reproductive system. It has been shown that estrogen is related to breast cancer development through binding to its receptors. In order to uncover the estrogen effects on adenosine receptor expression, estrogen-positive MCF-7 cells were used to treat with agonist and antagonist of estrogen and then the mRNA expression of adenosine receptor subtypes were evaluated. Estrogen-positive MCF-7 cells were treated with various concentrations of 17β estradiol (E2) as an estrogen agonist, and ICI 182,780 as an estrogen antagonist. The gene expression of adenosine receptor subtypes were detected by real time RT-PCR. The results of MTT assay showed that E2 increased cell viability in a dose dependent manner. The expression pattern of all adenosine receptor subtypes are as follow; A2b > A1 > A2a > A3 in untreated MCF-7 cells. Obtained results showed that E2 incubation at 0.001-0.01 μM led to up-regulation of A1ARs, A2aARs and A3ARs dose dependently. E2 at 0.001 μM also had no significant effect on A2bARs expression but, at higher doses induced a considerable decrease in mRNA A2bARs expression. Treatment with antagonist confirmed that up-regulation of these receptors is mediated by estrogen receptor. Taken together, our results indicate that treatment of MCF-7 cells with E2 led to up-regulation of adenosine receptors. However, these effects were partially restored by treatment with antagonist suggesting that such effects are mediated by estrogen receptors.

  20. Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Bostner, Josefine; Alayev, Anya; Berman, Adi Y; Fornander, Tommy; Nordenskjöld, Bo; Holz, Marina K; Stål, Olle

    2018-02-01

    Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer. Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ERα-positive cell lines was compared with that in ERα-negative cell lines. Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ERα signaling, here shown by a coupled increase of ERα phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ERα-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ERα-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. We present a connection between raptor localization to the nucleus and ERα-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.

  1. Estrogen receptor-positive primary squamous cell carcinoma of the breast

    Directory of Open Access Journals (Sweden)

    Abby M. Pribish, BS

    2017-06-01

    Full Text Available Pure primary squamous cell carcinoma of the breast (SCCB represents around 0.1% of breast carcinomas. Diagnosis requires independence from adjacent skin without metastatic disease. SCCB is often large at presentation with nonspecific mammographic and ultrasound findings. It is typically hormone receptor negative and aggressive. Mastectomy and adjuvant chemotherapy is the most common treatment, although treatment guidelines are not well established. We present a case of pure primary SCCB detected by high risk screening mammogram and treated with breast conserving surgery, chemotherapy, and radiation. We discuss clinical, radiologic, and pathologic findings.

  2. Estimated human excretion rates of natural estrogens calculated from their concentrations in raw municipal wastewater and its application.

    Science.gov (United States)

    Liu, Ze-Hua; Lu, Gui-Ning; Yin, Hua; Dang, Zhi

    2015-06-01

    Natural estrogens are important endocrine disrupting compounds (EDCs), which may pose adverse effects on our environment. To avoid time-consuming sample preparation and chemical analysis, estimation of their concentrations in municipal wastewater based on their human urine/feces excretion rates has been generally adopted. However, the data of excretion rates available are very limited and show significant difference among countries. In the context of increasing reporting on the concentrations of natural estrogens in municipal wastewater around the world, this study presented a simple method to estimate their human excretion rates based on the concentrations of natural estrogens in raw sewage. The estimated human excretion rates of natural estrogens among ten countries were obtained, which totally covered over 33 million population. Among these, Brazilians had the largest excretion rates with estrone (E1) and 17β-estradiol (E2) as 236.9 and 60 μg/day/P, respectively, while Iran had the lowest value of 2 μg/day/P for E1 and 0.5 μg/day/P for E2. The average estimated human excretion rates of E1, E2, and estriol (E3) are 17.3, 6.4, and 39.7 μg/day/P, respectively. When the estimated human excretion rates obtained were applied for prediction, the predicted results showed better accuracies than those based on human urinary/feces excretion rates. The method in this study is simple, cost-effective and time-saving, which may be widely applied.

  3. Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer

    International Nuclear Information System (INIS)

    Lee, Kiwon; Liu, Yin; Mo, Jun Qin; Zhang, Jinsong; Dong, Zhongyun; Lu, Shan

    2008-01-01

    Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERα)-mediated signaling axis. Immunohistochemistry analysis was performed in 43 breast cancer specimens and western blot analysis was used for human breast cancer cell lines to determine the expression level of Vav3 protein. The impact of Vav3 on breast cancer cell growth was determined by siRNA knockdown of Vav3 expression. The role of Vav3 in ERα activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERα activation. Finally, the interaction of Vav3 and ERα was assessed by GST pull-down analysis. We found that Vav3 was overexpressed in 81% of human breast cancer specimens, particularly in poorly differentiated lesions. Vav3 activated ERα partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERα activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERα. Consistent with its function for AR, the DH domain of Vav3 was essential for ERα activation. Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERα and enhances ERα activity. These findings suggest that Vav3 overexpression may aberrantly enhance ERα-mediated signaling axis and play a role in breast cancer development and/or progression

  4. Early estrogen-induced metabolic changes and their inhibition by actinomycin D and cycloheximide in human breast cancer cells: sup 31 P and sup 13 C NMR studies

    Energy Technology Data Exchange (ETDEWEB)

    Neeman, M.; Degani, H. (Weizmann Institute of Science, Rehovot (Israel))

    1989-07-01

    Metabolic changes following estrogen stimulation and the inhibition of these changes in the presence of actinomycin D and cycloheximide were monitored continuously in perfused human breast cancer T47D clone 11 cells with {sup 31}P and {sup 13}C NMR techniques. The experiments were performed by estrogen rescue of tamoxifen-treated cells. Immediately after perfusion with estrogen-containing medium, a continuous enhancement in the rates of glucose consumption, lactate production by glycolysis, and glutamate synthesis by the Krebs cycle occurred with a persistent 2-fold increase at 4 hr. Pretreatment with either actinomycin D or cycloheximide, at concentrations known to inhibit mRNA and protein synthesis, respectively, and simultaneous treatment with estrogen and each inhibitor prevented the estrogen-induced changes in glucose metabolism. This suggested that the observed estrogen stimulation required synthesis of mRNA and protein. These inhibitors also modulated several metabolic activities that were not related to estrogen stimulation. The observed changes in the in vivo kinetics of glucose metabolism may provide a means for the early detection of the response of human breast cancer cells to estrogen versus tamoxifen treatment.

  5. Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays

    International Nuclear Information System (INIS)

    Molina-Molina, Jose-Manuel; Escande, Aurelie; Pillon, Arnaud; Gomez, Elena; Pakdel, Farzad; Cavailles, Vincent; Olea, Nicolas; Ait-Aissa, Selim; Balaguer, Patrick

    2008-01-01

    Benzophenone (BP) derivatives, BP1 (2,4-dihydroxybenzophenone), BP2 (2,2',4,4'-tetrahydroxybenzophenone), BP3 (2-hydroxy-4-methoxybenzophenone), and THB (2,4,4'-trihydroxybenzophenone) are UV-absorbing chemicals widely used in pharmaceutical, cosmetics, and industrial applications, such as topical sunscreens in lotions and hair sprays to protect skin and hair from UV irradiation. Studies on their endocrine disrupting properties have mostly focused on their interaction with human estrogen receptor alpha (hERα), and there has been no comprehensive analysis of their potency in a system allowing comparison between hERα and hERβ activities. The objective of this study was to provide a comprehensive ER activation profile of BP derivatives using ER from human and fish origin in a battery of in vitro tests, i.e., competitive binding, reporter gene based assays, vitellogenin (Vtg) induction in isolated rainbow trout hepatocytes, and proliferation based assays. The ability to induce human androgen receptor (hAR)-mediated reporter gene expression was also examined. All BP derivatives tested except BP3 were full hERα and hERβ agonists (BP2 > THB > BP1) and displayed a stronger activation of hERβ compared with hERα, the opposite effect to that of estradiol (E 2 ). Unlike E 2 , BPs were more active in rainbow trout ERα (rtERα) than in hERα assay. All four BP derivatives showed anti-androgenic activity (THB > BP2 > BP1 > BP3). Overall, the observed anti-androgenic potencies of BP derivatives, together with their proposed greater effect on ERβ versus ERα activation, support further investigation of their role as endocrine disrupters in humans and wildlife

  6. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Tarulli, Gerard; Zarnke, Allison L; Bourgo, Ryan J; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G; Raj, Ganesh V; Hickey, Theresa E; Tilley, Wayne D; Greene, Geoffrey L

    2016-06-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored.

  7. N-3 poly-unsaturated fatty acids shift estrogen signaling to inhibit human breast cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Wenqing Cao

    Full Text Available Although evidence has shown the regulating effect of n-3 poly-unsaturated fatty acid (n-3 PUFA on cell signaling transduction, it remains unknown whether n-3 PUFA treatment modulates estrogen signaling. The current study showed that docosahexaenoic acid (DHA, C22:6, eicosapentaenoic acid (EPA, C20:5 shifted the pro-survival and proliferative effect of estrogen to a pro-apoptotic effect in human breast cancer (BCa MCF-7 and T47D cells. 17 β-estradiol (E2 enhanced the inhibitory effect of n-3 PUFAs on BCa cell growth. The IC50 of DHA or EPA in MCF-7 cells decreased when combined with E2 (10 nM treatment (from 173 µM for DHA only to 113 µM for DHA+E2, and from 187 µm for EPA only to 130 µm for EPA+E2. E2 also augmented apoptosis in n-3 PUFA-treated BCa cells. In contrast, in cells treated with stearic acid (SA, C18:0 as well as cells not treated with fatty acid, E2 promoted breast cancer cell growth. Classical (nuclear estrogen receptors may not be involved in the pro-apoptotic effects of E2 on the n-3 PUFA-treated BCa cells because ERα agonist failed to elicit, and ERα knockdown failed to block E2 pro-apoptotic effects. Subsequent studies reveal that G protein coupled estrogen receptor 1 (GPER1 may mediate the pro-apoptotic effect of estrogen. N-3 PUFA treatment initiated the pro-apoptotic signaling of estrogen by increasing GPER1-cAMP-PKA signaling response, and blunting EGFR, Erk 1/2, and AKT activity. These findings may not only provide the evidence to link n-3 PUFAs biologic effects and the pro-apoptotic signaling of estrogen in breast cancer cells, but also shed new insight into the potential application of n-3 PUFAs in BCa treatment.

  8. Differential expression of estrogen receptors alpha and beta mRNA during differentiation of human osteoblast SV-HFO cells

    NARCIS (Netherlands)

    J. Arts (Janine); J.M.M.F. Janssen (Josine); J.A. Gustafsson (Jan-Ake); C.W.G.M. Löwik (Clemens); H.A.P. Pols (Huib); J.P.T.M. van Leeuwen (Hans); G.G.J.M. Kuiper (George)

    1997-01-01

    textabstractEstrogens have been shown to be essential for maintaining a sufficiently high bone mineral density and ER alpha expression has been demonstrated in bone cells. Recently, a novel estrogen receptor, estrogen receptor beta (ERbeta) has been identified. Here

  9. Estrogenicity and androgenicity screening of PCB sulfate monoesters in human breast cancer MCF-7 cells

    OpenAIRE

    Flor, Susanne; He, Xianran; Lehmler, Hans-Joachim; Ludewig, Gabriele

    2015-01-01

    Recent studies identified PCB sulfate esters as a major product of PCB metabolism. Since hydroxy-PCBs (HO-PCBs), the immediate precursors of PCB sulfates and important contributors to PCB toxicity, were shown to have estrogenic activity, we investigated the estrogenicity/androgenicty of a series of PCB sulfate metabolites. We synthesized the five possible structural sulfate monoester metabolites of PCB 3, a congener shown to be biotransformed to sulfates, a sulfate ester of the paint-specific...

  10. The temporal expression of estrogen receptor alpha-36 and runx2 in human bone marrow derived stromal cells during osteogenesis

    International Nuclear Information System (INIS)

    Francis, W.R.; Owens, S.E.; Wilde, C.; Pallister, I.; Kanamarlapudi, V.; Zou, W.; Xia, Z.

    2014-01-01

    Highlights: • ERα36 is the predominant ERα isoform involved in bone regulation in human BMSC. • ERα36 mRNA is significantly upregulated during the process of osteogenesis. • The pattern of ERα36 and runx2 mRNA expression is similar during osteogenesis. • ERα36 appears to be co-localised with runx2 during osteogenesis. - Abstract: During bone maintenance in vivo, estrogen signals through estrogen receptor (ER)-α. The objectives of this study were to investigate the temporal expression of ERα36 and ascertain its functional relevance during osteogenesis in human bone marrow derived stromal cells (BMSC). This was assessed in relation to runt-related transcription factor-2 (runx2), a main modulatory protein involved in bone formation. ERα36 and runx2 subcellular localisation was assessed using immunocytochemistry, and their mRNA expression levels by real time PCR throughout the process of osteogenesis. The osteogenically induced BMSCs demonstrated a rise in ERα36 mRNA during proliferation followed by a decline in expression at day 10, which represents a change in dynamics within the culture between the proliferative stage and the differentiative stage. The mRNA expression profile of runx2 mirrored that of ERα36 and showed a degree subcellular co-localisation with ERα36. This study suggests that ERα36 is involved in the process of osteogenesis in BMSCs, which has implications in estrogen deficient environments

  11. Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A).

    Science.gov (United States)

    Hemachandra, L P; Madhubhani, P; Chandrasena, R; Esala, P; Chen, Shao-Nong; Main, Matthew; Lankin, David C; Scism, Robert A; Dietz, Birgit M; Pauli, Guido F; Thatcher, Gregory R J; Bolton, Judy L

    2012-01-01

    Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor-mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. ©2011 AACR.

  12. Hops (Humulus lupulus) inhibits Oxidative Estrogen Metabolism and Estrogen-Induced Malignant Transformation in Human Mammary Epithelial cells (MCF-10A)

    Science.gov (United States)

    Madhubhani, L.P.; Hemachandra, P.; Esala, R.; Chandrasena, P.; Chen, Shao-Nong; Main, Matthew; Lankin, David C.; Scism, Robert A.; Dietz, Birgit M.; Pauli, Guido F.; Thatcher, Gregory R. J.; Bolton, Judy L.

    2011-01-01

    Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus) as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor (ER) mediated hormonal pathway; and, the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Since OTC botanical HRT alternatives are in widespread use they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. LC-MS/MS analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; and 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nM). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. PMID:21997247

  13. Additive mixture effects of estrogenic chemicals in human cell-based assays can be influenced by inclusion of chemicals with differing effect profiles.

    Directory of Open Access Journals (Sweden)

    Richard Mark Evans

    Full Text Available A growing body of experimental evidence indicates that the in vitro effects of mixtures of estrogenic chemicals can be well predicted from the estrogenicity of their components by the concentration addition (CA concept. However, some studies have observed small deviations from CA. Factors affecting the presence or observation of deviations could include: the type of chemical tested; number of mixture components; mixture design; and assay choice. We designed mixture experiments that address these factors, using mixtures with high numbers of components, chemicals from diverse chemical groups, assays with different in vitro endpoints and different mixture designs and ratios. Firstly, the effects of mixtures composed of up to 17 estrogenic chemicals were examined using estrogenicity assays with reporter-gene (ERLUX and cell proliferation (ESCREEN endpoints. Two mixture designs were used: 1 a 'balanced' design with components present in proportion to a common effect concentration (e.g. an EC(10 and 2 a 'non-balanced' design with components in proportion to potential human tissue concentrations. Secondly, the individual and simultaneous ability of 16 potential modulator chemicals (each with minimal estrogenicity to influence the assay outcome produced by a reference mixture of estrogenic chemicals was examined. Test chemicals included plasticizers, phthalates, metals, PCBs, phytoestrogens, PAHs, heterocyclic amines, antioxidants, UV filters, musks, PBDEs and parabens. In all the scenarios tested, the CA concept provided a good prediction of mixture effects. Modulation studies revealed that chemicals possessing minimal estrogenicity themselves could reduce (negatively modulate the effect of a mixture of estrogenic chemicals. Whether the type of modulation we observed occurs in practice most likely depends on the chemical concentrations involved, and better information is required on likely human tissue concentrations of estrogens and of potential

  14. Distinct roles for aryl hydrocarbon receptor nuclear translocator and ah receptor in estrogen-mediated signaling in human cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Mark P Labrecque

    Full Text Available The activated AHR/ARNT complex (AHRC regulates the expression of target genes upon exposure to environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. Importantly, evidence has shown that TCDD represses estrogen receptor (ER target gene activation through the AHRC. Our data indicates that AHR and ARNT act independently from each other at non-dioxin response element sites. Therefore, we sought to determine the specific functions of AHR and ARNT in estrogen-dependent signaling in human MCF7 breast cancer and human ECC-1 endometrial carcinoma cells. Knockdown of AHR with siRNA abrogates dioxin-inducible repression of estrogen-dependent gene transcription. Intriguingly, knockdown of ARNT does not effect TCDD-mediated repression of estrogen-regulated transcription, suggesting that AHR represses ER function independently of ARNT. This theory is supported by the ability of the selective AHR modulator 3',4'-dimethoxy-α-naphthoflavone (DiMNF to repress estrogen-inducible transcription. Furthermore, basal and estrogen-activated transcription of the genes encoding cathepsin-D and pS2 are down-regulated in MCF7 cells but up-regulated in ECC-1 cells in response to loss of ARNT. These responses are mirrored at the protein level with cathepsin-D. Furthermore, knock-down of ARNT led to opposite but corresponding changes in estrogen-stimulated proliferation in both MCF7 and ECC-1 cells. We have obtained experimental evidence demonstrating a dioxin-dependent repressor function for AHR and a dioxin-independent co-activator/co-repressor function for ARNT in estrogen signalling. These results provide us with further insight into the mechanisms of transcription factor crosstalk and putative therapeutic targets in estrogen-positive cancers.

  15. Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

    Directory of Open Access Journals (Sweden)

    Mark Preciados

    2016-12-01

    Full Text Available During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA, polychlorinated biphenyls (PCBs, phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1 signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2 and

  16. Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases.

    Science.gov (United States)

    Preciados, Mark; Yoo, Changwon; Roy, Deodutta

    2016-12-13

    During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of

  17. Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    Full Text Available Cutaneous melanoma is an aggressive malignancy; its incidence is increasing worldwide and its prognosis remains poor. Clinical observations indicate that estrogen receptor β (ERβ is expressed in melanoma tissues and its expression decreases with tumor progression, suggesting its tumor suppressive function. These experiments were performed to investigate the effects of ERβ activation on melanoma cell growth.Protein expression was analyzed by Western blot and immunofluorescence assays. Cell proliferation was assessed by counting the cells by hemocytometer. ERβ transcriptional activity was evaluated by gene reporter assay. Global DNA methylation was analyzed by restriction enzyme assay and ERβ isoforms were identified by qRT-PCR. We demonstrated that ERβ is expressed in a panel of human melanoma cell lines (BLM, WM115, A375, WM1552. In BLM (NRAS-mutant cells, ERβ agonists significantly and specifically inhibited cell proliferation. ERβ activation triggered its cytoplasmic-to-nuclear translocation and transcriptional activity. Moreover, the antiproliferative activity of ERβ agonists was associated with an altered expression of G1-S transition-related proteins. In these cells, global DNA was found to be hypomethylated when compared to normal melanocytes; this DNA hypomethylation status was reverted by ERβ activation. ERβ agonists also decreased the proliferation of WM115 (BRAF V600D-mutant cells, while they failed to reduce the growth of A375 and WM1552 (BRAF V600E-mutant cells. Finally, we could observe that ERβ isoforms are expressed at different levels in the various cell lines. Specific oncogenic mutations or differential expression of receptor isoforms might be responsible for the different responses of cell lines to ERβ agonists.Our results demonstrate that ERβ is expressed in melanoma cell lines and that ERβ agonists differentially regulate the proliferation of these cells. These data confirm the notion that melanoma is a

  18. Putative Biomarkers and Targets of Estrogen Receptor Negative Human Breast Cancer

    Directory of Open Access Journals (Sweden)

    Stephen W. Byers

    2011-07-01

    Full Text Available Breast cancer is a progressive and potentially fatal disease that affects women of all ages. Like all progressive diseases, early and reliable diagnosis is the key for successful treatment and annihilation. Biomarkers serve as indicators of pathological, physiological, or pharmacological processes. Her2/neu, CA15.3, estrogen receptor (ER, progesterone receptor (PR, and cytokeratins are biomarkers that have been approved by the Food and Drug Administration for disease diagnosis, prognosis, and therapy selection. The structural and functional complexity of protein biomarkers and the heterogeneity of the breast cancer pathology present challenges to the scientific community. Here we review estrogen receptor-related putative breast cancer biomarkers, including those of putative breast cancer stem cells, a minor population of estrogen receptor negative tumor cells that retain the stem cell property of self renewal. We also review a few promising cytoskeleton targets for ER alpha negative breast cancer.

  19. Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer.

    Science.gov (United States)

    Matissek, Karina J; Onozato, Maristela L; Sun, Sheng; Zheng, Zongli; Schultz, Andrew; Lee, Jesse; Patel, Kristofer; Jerevall, Piiha-Lotta; Saladi, Srinivas Vinod; Macleay, Allison; Tavallai, Mehrad; Badovinac-Crnjevic, Tanja; Barrios, Carlos; Beşe, Nuran; Chan, Arlene; Chavarri-Guerra, Yanin; Debiasi, Marcio; Demirdögen, Elif; Egeli, Ünal; Gökgöz, Sahsuvar; Gomez, Henry; Liedke, Pedro; Tasdelen, Ismet; Tolunay, Sahsine; Werutsky, Gustavo; St Louis, Jessica; Horick, Nora; Finkelstein, Dianne M; Le, Long Phi; Bardia, Aditya; Goss, Paul E; Sgroi, Dennis C; Iafrate, A John; Ellisen, Leif W

    2018-03-01

    We sought to uncover genetic drivers of hormone receptor-positive (HR + ) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1 , and ESR1 , in 14% (24/173) of unselected patients with advanced HR + breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR + breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (fusions as frequent and potentially actionable drivers in HR + breast cancer. Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR + breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. ©2017 AACR. See related commentary by Natrajan et al., p. 272 See related article by Liu et al., p. 354 This article is highlighted in the In This Issue feature, p. 253 . ©2017 American Association for Cancer Research.

  20. Genetic Variants of GPER/GPR30, a Novel Estrogen-Related G Protein Receptor, Are Associated with Human Seminoma

    Directory of Open Access Journals (Sweden)

    Nicolas Chevalier

    2014-01-01

    Full Text Available Testicular germ cell tumors (TGCTs are the most common solid cancers in young men, with an increasing incidence over several years. However, their pathogenesis remains a matter of debate. Some epidemiological data suggest the involvement of both environmental and genetic factors. We reported two distinct effects of estrogens and/or xeno-estrogens on in vitro human seminoma-derived cells proliferation: (1 an antiproliferative effect via a classical estrogen receptor beta-dependent pathway, and (2 a promotive effect via a non-classical membrane G-protein-coupled receptor, GPR30/GPER, which is only overexpressed in seminomas, the most common TGCT. In order to explain this overexpression, we investigated the possible association of polymorphisms in the GPER gene by using allele-specific tetra-primer polymerase chain reaction performed on tissue samples from 150 paraffin-embedded TGCT specimens (131 seminomas, 19 non seminomas. Compared to control population, loss of homozygous ancestral genotype GG in two polymorphisms located in the promoter region of GPER (rs3808350 and rs3808351 was more frequent in seminomas but not in non-seminomas (respectively, OR = 1.960 (1.172–3.277 and 7.000 (2.747–17.840; p < 0.01. These polymorphisms may explain GPER overexpression and represent a genetic factor of susceptibility supporting the contribution of environmental GPER ligands in testicular carcinogenesis.

  1. Genetic Variants of GPER/GPR30, a Novel Estrogen-Related G Protein Receptor, Are Associated with Human Seminoma

    Science.gov (United States)

    Chevalier, Nicolas; Paul-Bellon, Rachel; Camparo, Philippe; Michiels, Jean-François; Chevallier, Daniel; Fénichel, Patrick

    2014-01-01

    Testicular germ cell tumors (TGCTs) are the most common solid cancers in young men, with an increasing incidence over several years. However, their pathogenesis remains a matter of debate. Some epidemiological data suggest the involvement of both environmental and genetic factors. We reported two distinct effects of estrogens and/or xeno-estrogens on in vitro human seminoma-derived cells proliferation: (1) an antiproliferative effect via a classical estrogen receptor beta-dependent pathway, and (2) a promotive effect via a non-classical membrane G-protein-coupled receptor, GPR30/GPER, which is only overexpressed in seminomas, the most common TGCT. In order to explain this overexpression, we investigated the possible association of polymorphisms in the GPER gene by using allele-specific tetra-primer polymerase chain reaction performed on tissue samples from 150 paraffin-embedded TGCT specimens (131 seminomas, 19 non seminomas). Compared to control population, loss of homozygous ancestral genotype GG in two polymorphisms located in the promoter region of GPER (rs3808350 and rs3808351) was more frequent in seminomas but not in non-seminomas (respectively, OR = 1.960 (1.172–3.277) and 7.000 (2.747–17.840); p < 0.01). These polymorphisms may explain GPER overexpression and represent a genetic factor of susceptibility supporting the contribution of environmental GPER ligands in testicular carcinogenesis. PMID:24451139

  2. Estrogen receptors (ERα versus ERβ): friends or foes in human biology?

    Science.gov (United States)

    Planey, Sonia Lobo; Kumar, Raj; Arnott, John A

    2014-02-01

    Most of the biological effects of estrogens are mediated via the estrogen receptors (ERs) at the level of gene regulation. Recently, new information regarding the role of ERs in physiology, pathology and the mechanisms through which estrogens bring about these functions has emerged. The physiological effects of estrogen are manifested through two ER isoforms - ERα and ERβ - which display distinct regions of sequence homology. The crystal structures of these receptors bound to their specific ligands (e.g. agonists or antagonists) have revealed much about how ligand binding alters receptor structure/conformation and the interaction with coactivators or corepressors as well as how it determines the cellular response to a ligand. ERs are involved in the variety of physiological and pathological activities and different cells and tissues have shown divergent responses to these two receptor isoforms. The discovery of sub-isoforms of ER alpha and beta has further complicated our understanding of how the interaction between ERs and its ligands contribute to the development of disease. Nevertheless, continuing efforts in the study of ERs have helped us to more clearly define their role in disease and to develop novel, ER-targeted therapeutics.

  3. Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters

    DEFF Research Database (Denmark)

    Ahmed, Shaaima; Valen, Eivind; Sandelin, Albin Gustav

    2009-01-01

    Recent studies have shown that activated aryl hydrocarbon receptor (AHR) induced the recruitment of estrogen receptor- (ER ) to AHR-regulated genes and that AHR is recruited to ER -regulated genes. However, these findings were limited to a small number of well-characterized AHR- or ER -responsive...

  4. Impact of polychlorinated biphenyls contamination on estrogenic activity in human male serum

    Czech Academy of Sciences Publication Activity Database

    Plíšková, M.; Vondráček, Jan; Canton, R. F.; Nera, J.; Kočan, Anton; Petrík, Ján; Trnovec, Tomáš; Sanderson, T.; van den Berg, Martin; Machala, M.

    2005-01-01

    Roč. 113, č. 10 (2005), s. 1277-1284 ISSN 0091-6765 Institutional research plan: CEZ:AV0Z50040507 Keywords : estrogenicity * dioxin -like activity * PCBs Subject RIV: BO - Biophysics Impact factor: 5.342, year: 2005

  5. Aptamer-Assisted Detection of the Altered Expression of Estrogen Receptor Alpha in Human Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Rajesh Ahirwar

    Full Text Available An increase in the expression of estrogen receptors (ER and the expanded population of ER-positive cells are two common phenotypes of breast cancer. Detection of the aberrantly expressed ERα in breast cancer is carried out using ERα-antibodies and radiolabelled ligands to make decisions about cancer treatment and targeted therapy. Capitalizing on the beneficial advantages of aptamer over the conventional antibody or radiolabelled ligand, we have identified a DNA aptamer that selectively binds and facilitates the detection of ERα in human breast cancer tissue sections. The aptamer is identified using the high throughput sequencing assisted SELEX screening. Biophysical characterization confirms the binding and formation of a thermodynamically stable complex between the identified DNA aptamer (ERaptD4 and ERα (Ka = 1.55±0.298×108 M(-1; ΔH = 4.32×104±801.1 cal/mol; ΔS = -108 cal/mol/deg. Interestingly, the specificity measurements suggest that the ERaptD4 internalizes into ERα-positive breast cancer cells in a target-selective manner and localizes specifically in the nuclear region. To harness these characteristics of ERaptD4 for detection of ERα expression in breast cancer samples, we performed the aptamer-assisted histochemical analysis of ERα in tissue samples from breast cancer patients. The results were validated by performing the immunohistochemistry on same samples with an ERα-antibody. We found that the two methods agree strongly in assay output (kappa value = 0.930, p-value <0.05 for strong ERα positive and the ERα negative samples; kappa value = 0.823, p-value <0.05 for the weak/moderate ER+ve samples, n = 20. Further, the aptamer stain the ERα-positive cells in breast tissues without cross-reacting to ERα-deficient fibroblasts, adipocytes, or the inflammatory cells. Our results demonstrate a significant consistency in the aptamer-assisted detection of ERα in strong ERα positive, moderate ERα positive and ERα negative

  6. Daidzein-estrogen interaction in the rat uterus and its effect on human breast cancer cell growth.

    Science.gov (United States)

    Gaete, Leonardo; Tchernitchin, Andrei N; Bustamante, Rodrigo; Villena, Joan; Lemus, Igor; Gidekel, Manuel; Cabrera, Gustavo; Astorga, Paola

    2012-12-01

    Sex hormone replacement therapy provides several advantages in the quality of life for climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk of cancer development in these organs. The lower incidence of mammary cancer in Asian women as compared with Western women has been attributed to high intake of soy isoflavones, including genistein. We have previously shown that genistein induces an estradiol-like hypertrophy of uterine cells, but does not induce cell proliferation, uterine eosinophilia, or endometrial edema. It also inhibits estradiol-induced mitosis in uterine cells and hormone-induced uterine eosinophilia and endometrial edema. Nevertheless, genistein stimulates growth of human breast cancer cells in culture; therefore, it is not an ideal estrogen for use in hormone replacement therapy (HRD). The present study investigated the effect of another soy isoflavone, daidzein (subcutaneous, 0.066 mg/kg body weight), in the same animal model, and its effect on responses induced by subsequent treatment (1 h later) with estradiol-17β (E(2); subcutaneous, 0.33 mg/kg body weight). In addition, we investigated the effects of daidzein (1 μg/mL) or E(2) on the growth of human breast cancer cells in culture. Results indicate that daidzein stimulates growth of breast cancer cells and potentiates estrogen-induced cell proliferation in the uterus. We suggest caution for the use of daidzein or formulas containing this compound in HRD. Future research strategies should be addressed in the search for new phytoestrogens that selectively inhibit cell proliferation in the uterus and breast.

  7. Daidzein–Estrogen Interaction in the Rat Uterus and Its Effect on Human Breast Cancer Cell Growth

    Science.gov (United States)

    Gaete, Leonardo; Bustamante, Rodrigo; Villena, Joan; Lemus, Igor; Gidekel, Manuel; Cabrera, Gustavo; Astorga, Paola

    2012-01-01

    Abstract Sex hormone replacement therapy provides several advantages in the quality of life for climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk of cancer development in these organs. The lower incidence of mammary cancer in Asian women as compared with Western women has been attributed to high intake of soy isoflavones, including genistein. We have previously shown that genistein induces an estradiol-like hypertrophy of uterine cells, but does not induce cell proliferation, uterine eosinophilia, or endometrial edema. It also inhibits estradiol-induced mitosis in uterine cells and hormone-induced uterine eosinophilia and endometrial edema. Nevertheless, genistein stimulates growth of human breast cancer cells in culture; therefore, it is not an ideal estrogen for use in hormone replacement therapy (HRD). The present study investigated the effect of another soy isoflavone, daidzein (subcutaneous, 0.066 mg/kg body weight), in the same animal model, and its effect on responses induced by subsequent treatment (1 h later) with estradiol-17β (E2; subcutaneous, 0.33 mg/kg body weight). In addition, we investigated the effects of daidzein (1 μg/mL) or E2 on the growth of human breast cancer cells in culture. Results indicate that daidzein stimulates growth of breast cancer cells and potentiates estrogen-induced cell proliferation in the uterus. We suggest caution for the use of daidzein or formulas containing this compound in HRD. Future research strategies should be addressed in the search for new phytoestrogens that selectively inhibit cell proliferation in the uterus and breast. PMID:23216111

  8. Human glutathione S-transferase P1-1 functions as an estrogen receptor α signaling modulator

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiyuan [Department of Biological Science, Sookmyung Women’s University, Seoul (Korea, Republic of); An, Byoung Ha [Department of Food and Nutrition, College of Life Science, Sookmyung Women’s University, Seoul (Korea, Republic of); Kim, Min Jung; Park, Jong Hoon [Department of Biological Science, Sookmyung Women’s University, Seoul (Korea, Republic of); Kang, Young Sook [Department of Pharmacy, College of Pharmacy, Sookmyung Women’s University, Seoul (Korea, Republic of); Chang, Minsun, E-mail: minsunchang@sm.ac.kr [Department of Medical and Pharmaceutical Science, College of Science, Sookmyung Women’s University, Seoul (Korea, Republic of)

    2014-09-26

    Highlights: • GSTP induces the classical ERα signaling event. • The functional GSTP is a prerequisite for GSTP-induced ERα transcription activity. • The expression of RIP140, a transcription cofactor, was inhibited by GSTP protein. • We propose the novel non-enzymatic role of GSTP. - Abstract: Estrogen receptor α (ERα) plays a crucial role in estrogen-mediated signaling pathways and exerts its action as a nuclear transcription factor. Binding of the ligand-activated ERα to the estrogen response element (ERE) is a central part of ERα-associated signal transduction pathways and its aberrant modulation is associated with many disease conditions. Human glutathione S-transferase P1-1 (GSTP) functions as an enzyme in conjugation reactions in drug metabolism and as a regulator of kinase signaling pathways. It is overexpressed in tumors following chemotherapy and has been associated with a poor prognosis in breast cancer. In this study, a novel regulatory function of GSTP has been proposed in which GSTP modulates ERE-mediated ERα signaling events. Ectopic expression of GSTP was able to induce the ERα and ERE-mediated transcriptional activities in ERα-positive but GSTP-negative MCF7 human breast cancer cells. This inductive effect of GSTP on the ERE-transcription activity was diminished when the cells express a mutated form of the enzyme or are treated with a GSTP-specific chemical inhibitor. It was found that GSTP inhibited the expression of the receptor interacting protein 140 (RIP140), a negative regulator of ERα transcription, at both mRNA and protein levels. Our study suggests a novel non-enzymatic role of GSTP which plays a significant role in regulating the classical ERα signaling pathways via modification of transcription cofactors such as RIP140.

  9. Mixture interactions of xenoestrogens with endogenous estrogens.

    Science.gov (United States)

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. These environmental estrogens originate from various sources including concentrated animal feedlot operations (CAFO), m...

  10. Estrogen-dependent regulation of human uterine natural killer cells promotes vascular remodelling via secretion of CCL2.

    Science.gov (United States)

    Gibson, D A; Greaves, E; Critchley, H O D; Saunders, P T K

    2015-06-01

    Does intrauterine biosynthesis of estrogen play an important role in early pregnancy by altering the function of uterine natural killer (uNK) cells? Estrogens directly regulate the function of human uNK cells by increasing uNK cell migration and secretion of uNK cell-derived chemokine (C-C motif) ligand 2 (CCL2) that critically facilitates uNK-mediated angiogenesis. uNK cells are a phenotypically distinct population of tissue-resident immune cells that regulate vascular remodelling within the endometrium and decidua. Recently we discovered that decidualisation of human endometrial stromal cells results in the generation of an estrogen-rich microenvironment in areas of decidualised endometrium. We hypothesize that intrauterine biosynthesis of estrogens plays an important role in early pregnancy by altering the function of uNK cells. This laboratory-based study used primary human uNK cells which were isolated from first trimester human decidua (n = 32). Primary uNK cells were isolated from first trimester human decidua using magnetic cell sorting. The impact of estrogens on uNK cell function was assessed. Isolated uNK cells were treated with estrone (E1, 10(-8) M) or estradiol (E2, 10(-8) M) alone or in combination with the anti-estrogen ICI 182 780 (ICI, 10(-6) M). uNK cell motility was assessed by transwell migration assay and time-lapse microscopy. Expression of chemokine receptors was assessed by quantitative PCR (qPCR) and immunohistochemistry, and angiogenic factors were assessed by qPCR and cytokine array. Concentrations of CCL2 in supernatants were measured by enzyme-linked immunosorbent assay. Angiogenesis was assessed in a human endometrial endothelial cell network formation assay. Treatment with either E1 or E2 increased uNK cell migration (P = 0.0092 and P = 0.0063, respectively) compared with control. Co-administration of the anti-estrogen ICI blocked the effects of E1 and E2 on cell migration. Concentrations of C-X-C chemokine receptor type 4 (CXCR4) m

  11. Identification of Estrogen Receptor Beta Binding Sites in the Human Genomes

    Science.gov (United States)

    2012-04-01

    suggesting an important role of ERβ in the development of the prostate as well as prostate cancer . Here we describe a study that thoroughly investigates the...considered the female sex hormone, is mainly produced by adipose tissue, adrenal glands, testicles and the prostate1. On the cellular and molecular level...E2 mainly exerts its effect via the two estrogen receptors, ERα and ERβ. ERα , as a marker for breast cancer , has been heavily studied, leading to

  12. Celecoxib affects estrogen sulfonation catalyzed by several human hepatic sulfotransferases, but does not stimulate 17-sulfonation in rat liver.

    Science.gov (United States)

    Ambadapadi, Sriram; Wang, Peter L; Palii, Sergiu P; James, Margaret O

    2017-09-01

    Celecoxib is known to alter the preferred position of SULT2A1-catalyzed sulfonation of 17β-estradiol (17β-E2) and other estrogens from the 3- to the 17-position. Understanding the effects of celecoxib on estrogen sulfonation is of interest in the context of the investigational use of celecoxib to treat breast cancer. This study examined the effects on celecoxib on cytosolic sulfotransferases in human and rat liver and on SULT enzymes known to be expressed in liver. Celecoxib's effects on the sulfonation of several steroids catalyzed by human liver cytosol were similar but not identical to those observed previously for SULT2A1. Celecoxib was shown to inhibit recombinant SULT1A1-catalyzed sulfonation of 10nM estrone and 4μM p-nitrophenol with IC 50 values of 2.6 and 2.1μM, respectively, but did not inhibit SULT1E1-catalyzed estrone sulfonation. In human liver cytosol, the combined effect of celecoxib and known SULT1A1 and 1E1 inhibitors, quercetin and triclosan, resulted in inhibition of 17β-E2-3-sulfonation such that the 17-sulfate became the major metabolite: this is of interest because the 17-sulfate is not readily hydrolyzed by steroid sulfatase to 17β-E2. Investigation of hepatic cytosolic steroid sulfonation in rat revealed that celecoxib did not stimulate 17β-E2 17-sulfonation in male or female rat liver as it does with human SULT2A1 and human liver cytosol, demonstrating that rat is not a useful model of this effect. In silico studies suggested that the presence of the bulky tryptophan residue in the substrate-binding site of the rat SULT2A homolog instead of glycine as in human SULT2A1 may explain this species difference. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Development and validation of fluorescent receptor assays based on the human recombinant estrogen receptor subtypes alpha and beta

    NARCIS (Netherlands)

    de boer, T; Otjens, D; Muntendam, A; Meulman, E; van Oostijen, M; Ensing, K

    2004-01-01

    This article describes the development and validation of two fluorescent receptor assays for the hRec-estrogen receptor subtypes alpha and beta. As a labelled ligand an autofluorescent phyto-estrogen (coumestrol) has been used. The estrogen receptor (ER) belongs to the nuclear receptor family, a

  14. ZEB1 is Estrogen Responsive In Vitro in Human Foreskin Cells and is Over Expressed in Penile Skin in Patients With Severe Hypospadias

    Science.gov (United States)

    Qiao, Liang; Tasian, Gregory E.; Zhang, Haiyang; Cunha, Gerald R.; Baskin, Laurence

    2012-01-01

    Purpose We determined the effect of estrogen on ZEB1 in vitro and tested the hypothesis that ZEB1 is over expressed in the penile skin of subjects with hypospadias. Materials and Methods Hs68 cells, a fibroblast cell line derived from human foreskin, were exposed to 0, 1, 10 and 100 nM estrogen, and the expression level of ZEB1 was assessed using reverse transcription real-time polymerase chain reaction, Western blot and immunocytochemical analysis. Next, preputial skin was prospectively collected from case and control subjects at hypospadias repair (37 cases) and circumcision (11). Hypospadias was classified as severe (13 cases) or mild (24) based on the position of the urethral meatus. ZEB1 expression was quantified using reverse transcription real-time polymerase chain reaction, Western blot and immunohistochemical analysis. Results Estrogen increased ZEB1 expression at the mRNA and protein levels in Hs68 cells in a concentration dependent fashion (p hypospadias had significantly higher ZEB1 mRNA levels and protein expression compared to controls or subjects with mild hypospadias (both p hypospadias had increased expression of ZEB1 in the basal layers of the preputial epidermis. Conclusions Estrogen increases ZEB1 expression in a human foreskin fibroblast cell line in vitro. Furthermore, ZEB1 is significantly over expressed in the penile skin of subjects with severe hypospadias. We propose that ZEB1 overexpression may contribute to development of hypospadias and may mediate the effect of estrogen on developing external male genitalia. PMID:21421232

  15. Xenoestrogens down-regulate aryl-hydrocarbon receptor nuclear translocator 2 mRNA expression in human breast cancer cells via an estrogen receptor alpha-dependent mechanism.

    Science.gov (United States)

    Qin, Xian-Yang; Zaha, Hiroko; Nagano, Reiko; Yoshinaga, Jun; Yonemoto, Junzo; Sone, Hideko

    2011-10-10

    Environmental chemicals with estrogenic activity, known as xenoestrogens, may cause impaired reproductive development and endocrine-related cancers in humans by disrupting endocrine functions. Aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) is believed to play important roles in a variety of physiological processes, including estrogen signaling pathways, that may be involved in the pathogenesis and therapeutic responses of endocrine-related cancers. However, much of the underlying mechanism remains unknown. In this study, we investigated whether ARNT2 expression is regulated by a range of representative xenoestrogens in human cancer cell lines. Bisphenol A (BPA), benzyl butyl phthalate (BBP), and 1,1,1-trichloro-2,2-bis(2-chlorophenyl-4-chlorophenyl)ethane (o,p'-DDT) were found to be estrogenic toward BG1Luc4E2 cells by an E-CALUX bioassay. ARNT2 expression was downregulated by BPA, BBP, and o,p'-DDT in a dose-dependent manner in estrogen receptor 1 (ESR1)-positive MCF-7 and BG1Luc4E2 cells, but not in estrogen receptor-negative LNCaP cells. The reduction in ARNT2 expression in cells treated with the xenoestrogens was fully recovered by the addition of a specific ESR1 antagonist, MPP. In conclusion, we have shown for the first time that ARNT2 expression is modulated by xenoestrogens by an ESR1-dependent mechanism in MCF-7 breast cancer cells. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  16. GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation.

    Directory of Open Access Journals (Sweden)

    Nicolas Chevalier

    Full Text Available BACKGROUND: Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30 mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium. The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation. RESULTS: We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells and germ cells (spermatogonia and spermatocytes. GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist and by siRNA invalidation. CONCLUSION: These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for

  17. GPR30, the Non-Classical Membrane G Protein Related Estrogen Receptor, Is Overexpressed in Human Seminoma and Promotes Seminoma Cell Proliferation

    Science.gov (United States)

    Chevalier, Nicolas; Vega, Aurélie; Bouskine, Adil; Siddeek, Bénazir; Michiels, Jean-François; Chevallier, Daniel; Fénichel, Patrick

    2012-01-01

    Background Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation. Results We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation. Conclusion These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas. PMID

  18. Estrogen receptor β-selective phytoestrogenic formulation prevents physical and neurological changes in a preclinical model of human menopause.

    Science.gov (United States)

    Zhao, Liqin; Mao, Zisu; Schneider, Lon S; Brinton, Roberta D

    2011-10-01

    As an alternative to estrogen therapy, the efficacy of an estrogen receptor β-selective phytoestrogenic (phyto-β-SERM) formulation to regulate climacteric symptoms and decline in brain responses associated with ovarian hormone loss in menopause was assessed. A phyto-β-SERM formulation-containing diet was compared with a commercial soy extract diet and a phytoestrogen-free base/control diet in an ovariectomized (OVX) mouse model of human menopause. Two treatment studies were conducted: (1) a 2-month study assessed the effects of experimental diets on tail skin temperature as a model of menopausal hot flashes, and (2) a 9-month study assessed the long-term impact of the diets on overall health, hair thinning/loss, spatial working memory, and associated protein expression in the hippocampus. The phyto-β-SERM diet prevented OVX-induced menopause-like changes including the rise in skin temperature, hair thinning/loss, deficit in spatial memory function, and reversed OVX-induced decline in the expression of hippocampal proteins involved in neural plasticity and β-amyloid degradation/clearance. The soy extract diet had no effect or exacerbated OVX-induced changes. Overall, the phyto-β-SERM diet induced physical and neurological responses comparable with ovary-intact mice, suggesting the therapeutic potential of the phyto-β-SERM formulation for the prevention/alleviation of climacteric symptoms and decline in brain responses induced by ovarian hormone loss, which provides the basis for further work in postmenopausal women.

  19. Estrogen receptor mediated effects of Cimicifuga extracts on human breast cancer cells.

    Science.gov (United States)

    Park, Joonwoo; Shim, Myeongkuk; Rhyu, Mee-Ra; Lee, YoungJoo

    2012-11-01

    Cimicifuga racemosa extracts have long been used to treat female reproductive disorders both in Asia and Europe. Here in this study, we examined the possible estrogen receptor (ER)alpha effects of Cimicifuga heracleifolia var. bifida ethanol extract (C-Ex), which has been used traditionally in Asia, in MCF-7 cells. The activity of C-Ex was characterized in a transient transfection system, using ERa and estrogen-responsive luciferase plasmids in HEK 293 cells and endogenous target genes were studied in MCF-7 cells. C-Ex failed to activate ERalpha and at a concentration of 0.005-0.5 mg/ml as examined by reporter activity. In addition, no statistically significant antiestrogenic activity was observed. However, to our interest, C-Ex enhanced expression of VEGF at 0.5 mg/ml concentration and repressed ERalpha both at the mRNA and protein levels in MCF-7 cells. These results suggested that C-Ex does not activate or inactivate ERalpha in a direct manner, but the extracts may affect factors in ER signal transduction pathway.

  20. Estrogen Injection

    Science.gov (United States)

    ... class of medications called hormones. It works by replacing estrogen that is normally produced by the body. ... your doctor about eating grapefruit and drinking grapefruit juice while using this medicine.

  1. Estrogen Test

    Science.gov (United States)

    ... and Iron-binding Capacity (TIBC, UIBC) Trichomonas Testing Triglycerides Troponin Tryptase Tumor Markers Uric Acid Urinalysis Urine ... in men and play a role in bone metabolism and growth in both sexes. Estrogen tests measure ...

  2. Expression pattern of G protein‑coupled estrogen receptor 1 (GPER) in human cumulus granulosa cells (CGCs) of patients with PCOS.

    Science.gov (United States)

    Zang, Lili; Zhang, Quan; Zhou, Yi; Zhao, Yan; Lu, Linlin; Jiang, Zhou; Peng, Zhen; Zou, Shuhua

    2016-06-01

    Estradiol mediates its actions by binding to classical nuclear receptors, estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and the non-classical G protein-coupled estrogen receptor 1(GPER). Several gene knockdown models have shown the importance of the receptors for growth of the oocyte and for ovulation. The aim of our study was to identify the pattern of GPER expression in human cumulus granulosa cells (CGCs) from ovarian follicles at different stages of oocyte maturation, and the differences of GPER expression between polycystic ovary syndrome (PCOS) patients and non-PCOS women. Thirty-eight cases of PCOS patients and a control group of thirty-two infertile women without PCOS were used in this study. GPER's location in CGCs was investigated by immunohistochemistry. Quantitative RT-PCR and western blot were used to identify the quantify GPER expression. Here we demonstrated that GPER was expressed in CGCs of both PCOS patients and non-PCOS women, and the expression of GPER was decreased significantly during oocyte maturation. But the expression levels of GPER in CGCs of PCOS patients and non-PCOS women were not significantly different. The data indicate that GPER may play a role during human oocyte maturation through its action in cumulus granulosa cells. AMHRIIs: anti-Mullerian hormone type II receptors; BMI: body mass index; CGCs: cumulus granulosa cells; COH: controlled ovarian hyperstimulation; E2: estradiol; EGFR: epidermal growth factor receptor; ER-α: estrogen receptor; ER-β: estrogen receptor β; FF: follicular fluid; FSH: follicle-stimulating hormone; GCs: granulosa cells; GPER: G protein-coupled estrogen receptor 1; GV: germinal vesicle; GVBD: germinal vesicle breakdown; HCG: human chorionic gonadotropin; IRS: immunoreactive score; IVF-ET: in vitro fertilization and embryo transfer; MI: metaphase I; MII: metaphase II; MAPK: mitogen-activated protein kinase; OCCCs: oocyte corona cumulus complexes; PCOS: polycystic ovarian syndrome; q

  3. The Z-isomer of 11 beta-methoxy-17 alpha-[123I]iodovinylestradiol is a promising radioligand for estrogen receptor imaging in human breast cancer

    NARCIS (Netherlands)

    Rijks, L. J.; Boer, G. J.; Endert, E.; de Bruin, K.; Janssen, A. G.; van Royen, E. A.

    1997-01-01

    The potential of both stereoisomers of 11 beta-methoxy-17 alpha-[123I] iodovinylestradiol (E- and Z-[123I]MIVE) as suitable radioligands for imaging of estrogen receptor (ER)-positive human breast tumours was studied. The 17 alpha-[123I]iodovinylestradiol derivatives were prepared stereospecifically

  4. Cell-specific biotransformation of benzophenone-2 and bisphenol-s in zebrafish and human in vitro models used for toxicity and estrogenicity screening.

    Science.gov (United States)

    Le Fol, Vincent; Aït-Aïssa, Selim; Cabaton, Nicolas; Dolo, Laurence; Grimaldi, Marina; Balaguer, Patrick; Perdu, Elisabeth; Debrauwer, Laurent; Brion, François; Zalko, Daniel

    2015-03-17

    Several human and fish bioassays have been designed to characterize the toxicity and the estrogenic activity of chemicals. However, their biotransformation capability (bioactivation/detoxification processes) is rarely reported, although this can influence the estrogenic potency of test compounds. The fate of two estrogenic chemicals, the UV filter benzophenone-2 (BP2) and the bisphenol A substitute bisphenol S (BPS) was deciphered in eight human and zebrafish in vitro cell models, encompassing hepatic and mammary cellular contexts. BP2 and BPS were metabolized into a variety of gluco- and sulfo-conjugated metabolites. Similar patterns of BP2 and BPS biotransformation were observed among zebrafish models (primary hepatocytes, ZFL and ZELH-zfER cell lines). Interestingly, metabolic patterns in zebrafish models and in the human hepatic cell line HepaRG shared many similarities, while biotransformation rates in cell lines widely used for estrogenicity testing (MELN and T47D-KBLuc) were quantitatively low and qualitatively different. This study provides new data on the comparative metabolism of BP2 and BPS in human and fish cellular models that will help characterize their metabolic capabilities, and underlines the relevance of using in vitro zebrafish-based bioassays when screening for endocrine disrupting chemicals.

  5. Estrogen regulation of testicular function

    Directory of Open Access Journals (Sweden)

    Akingbemi Benson T

    2005-09-01

    Full Text Available Abstract Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta in tissues of the reproductive tract; ii analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.

  6. Artonin E and Structural Analogs from Artocarpus Species Abrogates Estrogen Receptor Signaling in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Imaobong Etti

    2016-06-01

    Full Text Available The increasing rate of mortality ensued from breast cancer has encouraged research into safer and efficient therapy. The human Estrogen receptor α has been implicated in the majority of reported breast cancer cases. Molecular docking employing Glide, Schrodinger suite 2015, was used to study the binding affinities of small molecules from the Artocarpus species after their drug-like properties were ascertained. The structure of the ligand-binding domain of human Estrogen receptor α was retrieved from Protein Data Bank while the structures of compounds were collected from PubChem database. The binding interactions of the studied compounds were reported as well as their glide scores. The best glide scored ligand, was Artonin E with a score of −12.72 Kcal when compared to other studied phytomolecules and it evoked growth inhibition of an estrogen receptor positive breast cancer cells in submicromolar concentration (3.8–6.9 µM in comparison to a reference standard Tamoxifen (18.9–24.1 µM within the tested time point (24–72 h. The studied ligands, which had good interactions with the target receptor, were also drug-like when compared with 95% of orally available drugs with the exception of Artoelastin, whose predicted physicochemical properties rendered it less drug-like. The in silico physicochemical properties, docking interactions and growth inhibition of the best glide scorer are indications of the anti-breast cancer relevance of the studied molecules.

  7. Quantitative mapping of RNA-mediated nuclear estrogen receptor β interactome in human breast cancer cells

    Science.gov (United States)

    Giurato, Giorgio; Nassa, Giovanni; Salvati, Annamaria; Alexandrova, Elena; Rizzo, Francesca; Nyman, Tuula A.; Weisz, Alessandro; Tarallo, Roberta

    2018-03-01

    The nuclear receptor estrogen receptor 2 (ESR2, ERβ) modulates cancer cell proliferation and tumor growth, exerting an oncosuppressive role in breast cancer (BC). Interaction proteomics by tandem affinity purification coupled to mass spectrometry was previously applied in BC cells to identify proteins acting in concert with ERβ to control key cellular functions, including gene transcription, RNA splicing and post-transcriptional mRNA regulation. These studies revealed an involvement of RNA in ERβ interactome assembly and functions. By applying native protein complex purification followed by nano LC-MS/MS before and after in vitro RNA removal, we generated a large dataset of newly identified nuclear ERβ interactors, including a subset associating with the receptor via RNA bridging. These datasets will be useful to investigate further the role of ERβ, nuclear RNAs and the other proteins identified here in BC and other cell types.

  8. Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer.

    Science.gov (United States)

    Anbalagan, Muralidharan; Rowan, Brian G

    2015-12-15

    Estrogen receptor α (ERα) is a member of the nuclear receptor superfamily of transcription factors that regulates cell proliferation, differentiation and homeostasis in various tissues. Sustained exposure to estrogen/estradiol (E2) increases the risk of breast, endometrial and ovarian cancers. ERα function is also regulated by phosphorylation through various kinase signaling pathways that will impact various ERα functions including chromatin interaction, coregulator recruitment and gene expression, as well impact breast tumor growth/morphology and breast cancer patient response to endocrine therapy. However, many of the previously characterized ERα phosphorylation sites do not fully explain the impact of receptor phosphorylation on ERα function. This review discusses work from our laboratory toward understanding a role of ERα site-specific phosphorylation in ERα function and breast cancer. The key findings discussed in this review are: (1) the effect of site specific ERα phosphorylation on temporal recruitment of ERα and unique coactivator complexes to specific genes; (2) the impact of stable disruption of ERα S118 and S167 phosphorylation in breast cancer cells on eliciting unique gene expression profiles that culminate in significant effects on breast cancer growth/morphology/migration/invasion; (3) the Src kinase signaling pathway that impacts ERα phosphorylation to alter ERα function; and (4) circadian disruption by light exposure at night leading to elevated ERK1/2 and Src kinase and phosphorylation of ERα, concomitant with tamoxifen resistance in breast tumor models. Results from these studies demonstrate that even changes to single ERα phosphorylation sites can have a profound impact on ERα function in breast cancer. Future work will extend beyond single site phosphorylation analysis toward identification of specific patterns/profiles of ERα phosphorylation under different physiological/pharmacological conditions to understand how common

  9. Effects of xenoestrogens in human M1 and M2 macrophage migration, cytokine release, and estrogen-related signaling pathways.

    Science.gov (United States)

    Teixeira, Diana; Marques, Cláudia; Pestana, Diogo; Faria, Ana; Norberto, Sónia; Calhau, Conceição; Monteiro, Rosário

    2016-11-01

    Bisphenol A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and di(n-butyl)phthalate (DBP) are environmental estrogens that have been associated with a wide range of adverse health outcomes for which inflammation has also been hypothesized as a potentially involved mechanism and where macrophages play a central role. This study was carried out to evaluate if xenoestrogen (XE) treatment of classically (M1) or alternatively (M2) activated macrophages could affect their behavior. For this purpose, human peripheral blood monocyte-derived macrophages either unstimulated or activated with lipopolysaccharide (100 ng/mL, M1) or with interleukin (IL) 4 (15 ng/mL, M2) were treated with 17β-estradiol (E 2 ), BPA, DEHP and DBP alone or in combination with selective ERα or ERβ antagonists. Migratory capability, cytokine release, and estrogen-associated signaling pathways were evaluated to assess macrophage function. All tested XEs had a tendency to stimulate M2 migration, an effect that followed the same direction than E 2 . Moreover, all XEs significantly induced IL10 in M1 and decreased IL6 and globally decreased IL10, IL6, TNFα, and IL1β release by M2 macrophages. However, DEHP and DBP significantly increased IL1β release in M1 and M2 macrophages, respectively. Some of the effects described above were shown to be mediated by either ERα or ERβ and were simultaneous to modulation of NF-κB, AP1, JNK, or ERK signaling pathways. We provide new evidence of the effect of XE on macrophage behavior and their mechanisms with relevance to the understanding of the action of environmental chemicals on the immune system and inflammation-associated diseases. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1496-1509, 2016. © 2015 Wiley Periodicals, Inc.

  10. Estrogen regulation of TRPM8 expression in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Sevestre Henri

    2010-05-01

    Full Text Available Abstract Background The calcium-permeable cation channel TRPM8 (melastatin-related transient receptor potential member 8 is over-expressed in several cancers. The present study aimed at investigating the expression, function and potential regulation of TRPM8 channels by ER alpha (estrogen receptor alpha in breast cancer. Methods RT-PCR, Western blot, immuno-histochemical, and siRNA techniques were used to investigate TRPM8 expression, its regulation by estrogen receptors, and its expression in breast tissue. To investigate the channel activity in MCF-7 cells, we used the whole cell patch clamp and the calcium imaging techniques. Results TRPM8 channels are expressed at both mRNA and protein levels in the breast cancer cell line MCF-7. Bath application of the potent TRPM8 agonist Icilin (20 μM induced a strong outwardly rectifying current at depolarizing potentials, which is associated with an elevation of cytosolic calcium concentration, consistent with established TRPM8 channel properties. RT-PCR experiments revealed a decrease in TRPM8 mRNA expression following steroid deprivation for 48 and 72 hours. In steroid deprived medium, addition of 17-beta-estradiol (E2, 10 nM increased both TRPM8 mRNA expression and the number of cells which respond to Icilin, but failed to affect the Ca2+ entry amplitude. Moreover, silencing ERα mRNA expression with small interfering RNA reduced the expression of TRPM8. Immuno-histochemical examination of the expression of TRPM8 channels in human breast tissues revealed an over-expression of TRPM8 in breast adenocarcinomas, which is correlated with estrogen receptor positive (ER+ status of the tumours. Conclusion Taken together, these results show that TRPM8 channels are expressed and functional in breast cancer and that their expression is regulated by ER alpha.

  11. Estrogen regulation of TRPM8 expression in breast cancer cells

    International Nuclear Information System (INIS)

    Chodon, Dechen; Guilbert, Arnaud; Dhennin-Duthille, Isabelle; Gautier, Mathieu; Telliez, Marie-Sophie; Sevestre, Henri; Ouadid-Ahidouch, Halima

    2010-01-01

    The calcium-permeable cation channel TRPM8 (melastatin-related transient receptor potential member 8) is over-expressed in several cancers. The present study aimed at investigating the expression, function and potential regulation of TRPM8 channels by ER alpha (estrogen receptor alpha) in breast cancer. RT-PCR, Western blot, immuno-histochemical, and siRNA techniques were used to investigate TRPM8 expression, its regulation by estrogen receptors, and its expression in breast tissue. To investigate the channel activity in MCF-7 cells, we used the whole cell patch clamp and the calcium imaging techniques. TRPM8 channels are expressed at both mRNA and protein levels in the breast cancer cell line MCF-7. Bath application of the potent TRPM8 agonist Icilin (20 μM) induced a strong outwardly rectifying current at depolarizing potentials, which is associated with an elevation of cytosolic calcium concentration, consistent with established TRPM8 channel properties. RT-PCR experiments revealed a decrease in TRPM8 mRNA expression following steroid deprivation for 48 and 72 hours. In steroid deprived medium, addition of 17-beta-estradiol (E 2 , 10 nM) increased both TRPM8 mRNA expression and the number of cells which respond to Icilin, but failed to affect the Ca 2+ entry amplitude. Moreover, silencing ERα mRNA expression with small interfering RNA reduced the expression of TRPM8. Immuno-histochemical examination of the expression of TRPM8 channels in human breast tissues revealed an over-expression of TRPM8 in breast adenocarcinomas, which is correlated with estrogen receptor positive (ER + ) status of the tumours. Taken together, these results show that TRPM8 channels are expressed and functional in breast cancer and that their expression is regulated by ER alpha

  12. Long-term exposure to estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yu-Wei Chang

    Full Text Available Chemotherapy is the most common clinical option for treatment of breast cancer. However, the efficacy of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen responsive and the levels of ovarian estrogen vary among the breast cancer patients primarily between pre- and post-menopausal age. Whether this age-dependent variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is not known. Therefore, the objective of this study was to evaluate the effects of natural estrogen 17 beta-estradiol (E2 on the efficacy of chemotherapeutic drugs in breast cancer cells. Estrogen responsive MCF-7 and T47D breast cancer cells were long-term exposed to 100 pg/ml estrogen, and using these cells the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased sensitivities of doxorubicin and cisplatin in estrogen-exposed MCF-7 and T47D cells as compared to their respective control cells. Gene expression analysis of cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-aza-2-deoxycytidine and Trichostatin A prior to doxorubicin and cisplatin treatments. The 5-aza-2 deoxycytidine pre-treatment significantly decreased the estrogen-induced efficacy of doxorubicin and cisplatin, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In summary, the results of this study revealed that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the chemotherapy strategies for

  13. Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK dependent pathway in human endometrial cancer cells.

    Directory of Open Access Journals (Sweden)

    Chunxiao Zhou

    Full Text Available Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2 induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs, and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.

  14. Delta(9)-tetrahydrocannabinol inhibits 17beta-estradiol-induced proliferation and fails to activate androgen and estrogen receptors in MCF7 human breast cancer cells.

    Science.gov (United States)

    von Bueren, A O; Schlumpf, M; Lichtensteiger, W

    2008-01-01

    Delta(9)-tetrahydrocannabinol (THC) exerts palliative effects in cancer patients, but produces adverse effects on the endocrine and reproductive systems. Experimental evidence concerning such effects is controversial. Whether THC exhibits estrogenic or androgenic activity in vitro was investigated. Estrogenic effects of THC were analyzed in vitro by measuring the proliferation of estrogen-sensitive MCF7 cells. Androgenic activity was investigated by the A-Screen assay that measures androgen-dependent inhibition of proliferation of the androgen receptor (AR)-positive human mammary carcinoma cell line, MCF7-AR1. In contrast to 17beta-estradiol, included as positive control with an EC50 value (concentration required for 50% of maximal 17beta-estradiol-induced proliferation) of 1.00 x 10(-12) M, THC failed to induce cell proliferation in the MCF7 cell line at concentrations between 10(-13) and 10(-4) M. THC inhibited 17beta-estradiol-induced proliferation in wild-type MCF7 and MCF7-AR1 cells, with an IC50 value of 2.6 x 10(-5) M and 9 x 10(-6) M, respectively. THC failed to act as an estrogen, but antagonized 17beta-estradiol-induced proliferation. This effect was independent of the AR expression level.

  15. Spontaneous feline mammary intraepithelial lesions as a model for human estrogen receptor- and progesterone receptor-negative breast lesions

    International Nuclear Information System (INIS)

    Burrai, Giovanni P; Mohammed, Sulma I; Miller, Margaret A; Marras, Vincenzo; Pirino, Salvatore; Addis, Maria F; Uzzau, Sergio; Antuofermo, Elisabetta

    2010-01-01

    Breast cancer is the most frequently diagnosed cancer in women. Intraepithelial lesions (IELs), such as usual ductal hyperplasia (UH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) are risk factors that predict a woman's chance of developing invasive breast cancer. Therefore, a comparative study that establishes an animal model of pre-invasive lesions is needed for the development of preventative measures and effective treatment for both mammary IELs and tumors. The purpose of this study was to characterize the histologic and molecular features of feline mammary IELs and compare them with those in women. Formalin-fixed, paraffin-embedded specimens (n = 205) from 203 female cats with clinical mammary disease were retrieved from the archives of the Purdue University Animal Disease Diagnostic Laboratory and Veterinary Teaching Hospital (West Lafayette, IN), and the Department of Pathology and Veterinary Clinic, School of Veterinary Medicine (Sassari, Italy). Histologic sections, stained with hematoxylin and eosin (HE), were evaluated for the presence of IELs in tissue adjacent to excised mammary tumors. Lesions were compared to those of humans. Immunohistochemistry for estrogen receptor (ER-alpha), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2/neu) and Ki-67 was performed in IELs and adjacent tumor tissues. Intraepithelial lesions were found in 57 of 203 (28%) feline mammary specimens and were categorized as UH (27%), ADH (29%), and DCIS (44%). Most IELs with atypia (ADH and DCIS) were associated with mammary cancer (91%), whereas UH was associated with benign lesions in 53% of cases. Feline IELs were remarkably similar to human IELs. No ER or PR immunoreactivity was detected in intermediate-grade or high-grade DCIS or their associated malignant tumors. HER-2 protein overexpression was found in 27% of IELs. The remarkable similarity of feline mammary IELs to those of humans, with the tendency to lose hormone

  16. Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells

    International Nuclear Information System (INIS)

    Spink, Barbara C.; Bennett, James A.; Pentecost, Brian T.; Lostritto, Nicole; Englert, Neal A.; Benn, Geoffrey K.; Goodenough, Angela K.; Turesky, Robert J.; Spink, David C.

    2009-01-01

    The cumulative exposure to estrogens is an important determinant in the risk of breast cancer, yet the full range of mechanisms involving estrogens in the genesis and progression of breast cancer remains a subject of debate. Interactions of estrogens and environmental toxicants have received attention as putative factors contributing to carcinogenesis. Mechanistic studies have demonstrated interactions between estrogen receptor α (ERα) and the aryl hydrocarbon receptor (AhR), with consequences on the genes that they regulate. Many studies of ERα and AhR-mediated effects and crosstalk between them have focused on the initial molecular events. In this study, we investigated ERα- and AhR-mediated effects in long-term estrogen exposed (LTEE) MCF-7 human breast cancer cells, which were obtained by continuous culturing for at least 12 weeks in medium supplemented with 1 nM of 17β-estradiol (E 2 ). With these LTEE cells and with parallel control cells cultured without E 2 supplementation, we performed an extensive study of cytochrome P450 (CYP) induction, carcinogen bioactivation, global gene expression, and tumorigenicity in immunocompromised mice. We found that LTEE cells, in comparison with control cells, had higher levels of AhR mRNA and protein, greater responsiveness for AhR-regulated CYP1A1 and CYP1B1 induction, a 6-fold higher initial level of benzo(a)pyrene-DNA adducts as determined by liquid chromatography tandem mass spectrometry, marked differences in the expression of numerous genes, and a higher rate of E 2 -dependent tumor growth as xenografts. These studies indicate that LTEE causes adaptive responses in MCF-7 cells, which may reflect processes that contribute to the overall carcinogenic effect of E 2 .

  17. Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients.

    Science.gov (United States)

    Hertz, Daniel L; Henry, N Lynn; Rae, James M

    2017-04-01

    The third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are highly effective for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. AIs inhibit the aromatase (CYP19A1)-mediated production of estrogens. Most patients taking AIs achieve undetectable blood estrogen concentrations resulting in drug efficacy with tolerable side effects. However, some patients have suboptimal outcomes, which may be due, in part, to inherited germline genetic variants. This review summarizes published germline genetic associations with AI treatment outcomes including systemic AI concentrations, estrogenic response to AIs, AI treatment efficacy and AI treatment toxicities. Significant associations are highlighted with commentary about prioritization for future validation to identify pharmacogenetic predictors of AI treatment outcomes that can be used to inform personalized treatment decisions in patients with estrogen receptor-positive breast cancer.

  18. Dose-dependent effect of 17 beta-estradiol determined by growth curves and flow cytometric DNA analysis of a human breast carcinoma (T61) grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Vindeløv, L

    1985-01-01

    An estrogen and progesterone receptor-positive human breast carcinoma (T61) grown in nude mice was exposed to 1.0, 0.1, 0.01, and 0.001 mg 17 beta-estradiol. These doses resulted in serum peak concentrations (day 1) of estradiol ranging from 3.5 X 10(-8) to 6.9 X 10(-10) M. The effect of the trea......An estrogen and progesterone receptor-positive human breast carcinoma (T61) grown in nude mice was exposed to 1.0, 0.1, 0.01, and 0.001 mg 17 beta-estradiol. These doses resulted in serum peak concentrations (day 1) of estradiol ranging from 3.5 X 10(-8) to 6.9 X 10(-10) M. The effect...

  19. Obesity is associated with a poorer prognosis in women with hormone receptor positive breast cancer.

    Science.gov (United States)

    Robinson, Penelope J; Bell, Robin J; Davis, Susan R

    2014-11-01

    Whether moderate to severe obesity (body mass index (BMI)≥30 to women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (women, mean age, 58.4±11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR=1.71, 95%CI, 1.12-2.62, p=0.014), disease beyond Stage 1 (HR=2.87, 95% CI 1.73-4.75, pobesity (HR 3.23, 95%CI 1.48-7.03, p=0.003) and OAET use (HR 0.41, 95%CI 0.17-0.98, p=0.046) were significantly associated with an event. Moderate to severe obesity is associated with a poorer invasive breast cancer prognosis; this is also true for women with Stage 1 disease, and is independent of age and treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer

    DEFF Research Database (Denmark)

    Warren, Helen; Dudbridge, Frank; Fletcher, Olivia

    2012-01-01

    Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).......Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686)....

  1. Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients

    NARCIS (Netherlands)

    van Nes, Johanna G. H.; de Kruijf, Esther M.; Putter, Hein; Faratian, Dana; Munro, Alison; Campbell, Fiona; Smit, Vincent T. H. B. M.; Liefers, Gerrit-Jan; Kuppen, Peter J. K.; van de Velde, Cornelis J. H.; Bartlett, John M. S.

    Epithelial mesenchymal transition (EMT) plays an important role in the development of metastases. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by transcription factors, such as SNAIL, SLUG, and TWIST. We examined the prognostic value of

  2. A Novel Approach for the Identification of Pharmacophores through Differential Toxicity Analysis of Estrogen Receptor Positive and Negative Cell Lines

    National Research Council Canada - National Science Library

    Cunningham, Albert R; Day, Billy W

    2007-01-01

    .... This project was essential to my obtaining an appointment as an Associate Professor of Medicine at the University of Louisville's James Graham Brown Cancer Center along with significant startup...

  3. A Novel Approach for the Identification of Pharmacophores Through Differential Toxicity Analysis of Estrogen Receptor Positive and Negative Cell Lines

    National Research Council Canada - National Science Library

    Cunningham, Albert R

    2008-01-01

    .... This project was essential to my obtaining an appointment as an Associate Professor of Medicine at the University of Louisville's James Graham Brown Cancer Center, along with significant startup...

  4. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

    NARCIS (Netherlands)

    Stacey, S.N.; Manolescu, A.; Sulem, P.; Rafnar, T.; Gudmundsson, J.; Gudjonsson, S.A.; Masson, G.; Jakobsdottir, M.; Thorlacius, S.; Helgason, A.; Aben, K.K.H.; Strobbe, L.J.; Albers-Akkers, M.T.; Swinkels, D.W.; Henderson, B.E.; Kolonel, L.N.; Marchand, L. le; Millastre, E.; Andres, R.; Godino, J.; Garcia-Prats, M.D.; Polo, E.; Tres, A.; Mouy, M.; Saemundsdottir, J.; Backman, V.M.; Gudmundsson, L.; Kristjansson, K.; Bergthorsson, J.T.; Kostic, J.; Frigge, M.L.; Geller, F.; Gudbjartsson, D.F.; Sigurdsson, H.; Jonsdottir, T.; Hrafnkelsson, J.; Johannsson, J.; Sveinsson, T.; Myrdal, G.; Grimsson, H.N.; Jonsson, T.; Holst, S. von; Werelius, B.; Margolin, S.; Lindblom, A.; Mayordomo, J.I.; Haiman, C.A.; Kiemeney, L.A.L.M.; Johannsson, O.T.; Gulcher, J.R.; Thorsteinsdottir, U.; Kong, A.; Stefansson, K.

    2007-01-01

    Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then

  5. 17β-estradiol-induced ACSL4 protein expression promotes an invasive phenotype in estrogen receptor positive mammary carcinoma cells.

    Science.gov (United States)

    Belkaid, Anissa; Ouellette, Rodney J; Surette, Marc E

    2017-04-01

    Long chain acyl-CoA synthase-4 (ACSL4) expression has been associated with an aggressive phenotype in breast carcinoma cells, whereas its role in ERα-positive breast cancer has not been studied. ACSL4 prefers 20-carbon polyunsaturated fatty acid (PUFA) substrates, and along with other ACSLs has been associated with cellular uptake of exogenous fatty acids. 17β-estradiol induces proliferation and invasive capacities in ERα+ve breast carcinoma that is associated with modifications of cellular lipid metabolism. In this study, treatment of steroid-starved ERα-positive MCF-7 and T47D mammary carcinoma cells with 17β-estradiol resulted in increased cellular uptake of the PUFA arachidonic acid (AA) and eicosapentaenoic acid (EPA), important building blocks for cellular membranes, and increased ACSL4 protein levels. There was no change in the expression of the ACSL1, ACSL3 and ACSL6 protein isotypes. Increased ACSL4 protein expression was not accompanied by changes in ACSL4 mRNA expression, but was associated with a significant increase in the protein half-life compared to untreated cells. ERα silencing reversed the impact of 17β-estradiol on ACSL4 protein levels and half-life. Silencing of ACSL4 eliminated the 17β-estradiol-induced increase in AA and EPA uptake, as well as the 17β-estradiol-induced cell migration, proliferation and invasion capacities. ASCL4 silencing also prevented the 17β-estradiol induced increases in p-Akt and p-GSK3β, and decrease in E-cadherin expression, important events in epithelial to mesenchymal transition. Taken together, these results demonstrate that ACSL4 is a target of 17β-estradiol-stimulated ERα and is required for the cellular uptake of exogenous PUFA and the manifestation of a more malignant phenotype in ERα+ve breast carcinoma cells. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Trade-off preferences regarding adjuvant endocrine therapy among women with estrogen receptor-positive breast cancer.

    NARCIS (Netherlands)

    Wouters, H.; Maatman, G.A.; Dijk, L. van; Bouvy, M.L.; Vree, R.; Geffen, E.C.G. van; Nortier, J.W.; Stiggelbout, A.M.

    2013-01-01

    Background: There is substantial nonadherence to effective adjuvant endocrine therapy for breast cancer prevention. We therefore examined patients' trade-offs between the efficacy, side-effects, and regimen duration, and whether trade-offs predicted nonadherence. Patients and methods: Trade-offs

  7. Trade-off preferences regarding adjuvant endocrine therapy among women with estrogen receptor-positive breast cancer

    NARCIS (Netherlands)

    Wouters, H; Maatman, G A; Van Dijk, L; Bouvy, M L; Vree, R; Van Geffen, E C G; Nortier, J W; Stiggelbout, A M

    BACKGROUND: There is substantial nonadherence to effective adjuvant endocrine therapy for breast cancer prevention. We therefore examined patients' trade-offs between the efficacy, side-effects, and regimen duration, and whether trade-offs predicted nonadherence. PATIENTS AND METHODS: Trade-offs

  8. Aurora kinase A as a possible marker for endocrine resistance in early estrogen receptor positive breast cancer

    DEFF Research Database (Denmark)

    Lykkesfeldt, Anne E; Iversen, Benedikte R; Jensen, Maj-Britt

    2018-01-01

    BACKGROUND: Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting. MATERIAL AND METHODS: Archival tumor tissue...... in 980 tumors and semi quantitively scored into three groups; negative/weak, moderate and high. The Aurora A expression levels were compared to other clinico-pathological parameters and outcome, defined as disease-free survival (DFS) and overall survival (OS). RESULTS: High expression of Aurora...

  9. Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor-Positive Tumors

    Directory of Open Access Journals (Sweden)

    Maarten Brom

    2011-03-01

    Full Text Available In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0 showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET, which could improve image quality. Targeting of cholecystokinin-2 (CCK2/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g, indicating CCK2/gastrin receptor-mediated uptake (p = .0005. The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.

  10. Differential recruitment of co-regulatory proteins to the human estrogen receptor 1 in response to xenoestrogens.

    Science.gov (United States)

    Smith, L Cody; Clark, Jessica C; Bisesi, Joseph H; Ferguson, P Lee; Sabo-Attwood, Tara

    2016-09-01

    The diverse biological effects of xenoestrogens may be explained by their ability to differentially recruit co-regulatory proteins to the estrogen receptor (ER). We employed high-throughput receptor affinity binding and co-regulatory protein recruitment screening assays based on fluorescence polarization and time resolved florescence resonance energy transfer (TR-FRET), respectively, to assess xenoestrogen-specific binding and co-regulatory protein recruitment to the ER. Then we used a functional proteomic assay based on co-immunoprecipitation of ER-bound proteins to isolate and identify intact co-regulatory proteins recruited to a ligand-activated ER. Through these approaches, we revealed differential binding affinity of bisphenol-A (BPA) and genistein (GEN) to the human ERα (ESR1) and ligand-dependent recruitment of SRC-1 and SRC-3 peptides. Recruitment profiles were variable for each ligand and in some cases were distinct compared to 17β-estradiol (E2). For example, E2 and GEN recruited both SRC-1 and -3 peptides whereas BPA recruited only SRC-1 peptides. Results of the functional proteomic assay showed differential recruitment between ligands where E2 recruited the greatest number of proteins followed by BPA then GEN. A number of proteins share previously identified relationships with ESR1 as determined by STRING analysis. Although there was limited overlap in proteins identified between treatments, all ligands recruited proteins involved in cell growth as determined by subnetwork enrichment analysis (p<0.05). A comparative, in silico analysis revealed that fewer interactions exist between zebrafish (Danio rerio) esr1 and zebrafish orthologs of proteins identified in our functional proteomic analysis. Taken together these results identify recruitment of known and previously unknown co-regulatory proteins to ESR1 and highlight new methods to assay recruitment of low abundant and intact, endogenous co-regulatory proteins to ESR1 or other nuclear receptors, in

  11. Differential recruitment of co-regulatory proteins to the human estrogen receptor 1 in response to xenoestrogens☆,☆☆

    Science.gov (United States)

    2016-01-01

    The diverse biological effects of xenoestrogens may be explained by their ability to differentially recruit co-regulatory proteins to the estrogen receptor (ER). We employed high-throughput receptor affinity binding and co-regulatory protein recruitment screening assays based on fluorescence polarization and time resolved florescence resonance energy transfer (TR-FRET), respectively, to assess xenoestrogen-specific binding and co-regulatory protein recruitment to the ER. Then we used a functional proteomic assay based on co-immunoprecipitation of ER-bound proteins to isolate and identify intact co-regulatory proteins recruited to a ligand-activated ER. Through these approaches, we revealed differential binding affinity of bisphenol-A (BPA) and genistein (GEN) to the human ERα (ESR1) and ligand-dependent recruitment of SRC-1 and SRC-3 peptides. Recruitment profiles were variable for each ligand and in some cases were distinct compared to 17β-estradiol (E2). For example, E2 and GEN recruited both SRC-1 and -3 peptides whereas BPA recruited only SRC-1 peptides. Results of the functional proteomic assay showed differential recruitment between ligands where E2 recruited the greatest number of proteins followed by BPA then GEN. A number of proteins share previously identified relationships with ESR1 as determined by STRING analysis. Although there was limited overlap in proteins identified between treatments, all ligands recruited proteins involved in cell growth as determined by subnetwork enrichment analysis (p < 0.05). A comparative, in silico analysis revealed that fewer interactions exist between zebrafish (Danio rerio) esr1 and zebrafish orthologs of proteins identified in our functional proteomic analysis. Taken together these results identify recruitment of known and previously unknown co-regulatory proteins to ESR1 and highlight new methods to assay recruitment of low abundant and intact, endogenous co-regulatory proteins to ESR1 or other nuclear receptors, in

  12. Estrogen and Bazedoxifene

    Science.gov (United States)

    ... medications called estrogen agonist–antagonists. Estrogen works by replacing estrogen that is normally produced by the body. ... eat large amounts of grapefruit or drink grapefruit juice while taking this medication.

  13. Role of Nuclear Matrix in Estrogen Regulated Gene Expression in Human Breast Cancer Cells

    Science.gov (United States)

    1998-08-01

    then replacing the rat GR with the human ER coding region in pSG5-HEGO, previously mutated with the Chameleon site-directed mutagenesis kit (Stratagene... mutation which alters its hormone binding properties. EMBO J. 8, 1981-1986. Tsai, M.J. and O’Malley, B.W. (1994). Molecular mechanisms of action of steroid

  14. Estrogen Metabolism and Breast Cancer Risk – A Review | Okobia ...

    African Journals Online (AJOL)

    This paradigm shift is necessitated by evidence of estrogen induced carcinogenesis in several animal and human models following exposure to these estrogen metabolites. This review examines some of the available evidence relating these estrogen metabolites to animal and human breast carcinogenesis. African Journal ...

  15. Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents

    OpenAIRE

    King, Roberta S.; Ghosh, Anasuya A.; Wu, Jinfang

    2006-01-01

    This study was initiated on the hypothesis that aryl acetic acid and aryl carboxylic acid-containing drugs would inhibit human phenol sulfotransferase (SULT1A1), and that isoform selectivity would depend on the interaction of the aryl portion of the molecule with the acceptor binding site of the sulfotransferase. This hypothesis was based on results with the rat orthologue enzyme showing that oxidation of phenolic substrates to carboxylic acid derivatives resulted in competitive inhibition of...

  16. In-vitro effect of estrogen-antagonist on motility and penetration ability of human spermatozoa.

    Science.gov (United States)

    Allag, I S; Rangari, K

    1997-08-01

    Antiestrogens affect spermatozoa through their action on Leydig and Sertoli cells. Direct effect of antiestrogens namely tamoxifen and centchroman in concentration of 1, 2.5, 5, 10 and 20 micrograms/ml in incubation medium was determined on motility and penetration ability of human spermatozoa. Motility (%) was invariably reduced after 15, 30 and 60 min. of incubation. Addition of 17 beta-estradiol to medium with antagonist caused inhibition of motility in dose related manner. The distance travelled by spermatozoa treated with tamoxifen or centchroman in media was reduced by 30% and addition of estradiol along with antiestrogen reduced it to 50% compared to that of untreated spermatozoa.

  17. Evaluation of the stereoselective biotransformation of permethrin in human liver microsomes: contributions of cytochrome P450 monooxygenases to the formation of estrogenic metabolites.

    Science.gov (United States)

    Lavado, Ramon; Li, Jiwen; Rimoldi, John M; Schlenk, Daniel

    2014-04-21

    Permethrin (PM) is a pyrethroid insecticide that exists as 4 enantiomers. Biotransformation of PM to estrogen receptor agonists (3-phenoxybenzyl alcohol (PBOH) and 3-(4'-hydroxyphenoxy)-benzyl alcohol (3,4 PBOH)) has been shown to be stereoselective in other vertebrate species. This study evaluated the biotransformation of PM enantiomers in human liver microsomes and with recombinant CYP3A4 and CYP2C19. PBOH and 3,4 PBOH were the only metabolites detected from in vitro incubations including each of the 4 enantiomers of PM with 1R-trans PM having the most efficient NADPH-catalyzed biotransformation to both metabolites. Coincubation with the CYP inhibitor ketoconazole and time course experiments with liver microsomes and recombinant CYP2C19 and CYP3A4 indicated CYP-catalyzed stereoselective cleavage of the ester followed by 4-hydoxylation to 3,4' PBOH. These data indicate potential dispositional differences may occur with PM enantiomers and a shift in putative molecular targets. While cleavage of pyrethroid esters lead to detoxification of the acute neurological effects, formation of the benzyl alcohol and hydroxylated metabolite may lead to estrogenic responses, since each of these metabolites are estrogen receptor ligands. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Medroxyprogesterone acetate attenuates estrogen-induced nitric oxide production in human umbilical vein endothelial cells

    International Nuclear Information System (INIS)

    Oishi, Akira; Ohmichi, Masahide; Takahashi, Kazuhiro; Takahashi, Toshifumi; Mori-Abe, Akiko; Kawagoe, Jun; Otsu, Reiko; Mochizuki, Yoshiko; Inaba, Noriyuki; Kurachi, Hirohisa

    2004-01-01

    We report the novel observation that medroxyprogesterone acetate (MPA) attenuates the induction by 17β estradiol (E2) of both nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in human umbilical vein endothelial cells. Although MPA had no effect on basal NO production or basal eNOS phosphorylation or activity, it attenuated the E2-induced NO production and eNOS phosphorylation and activity. Moreover, we examined the mechanism by which MPA attenuated the E2-induced NO production and eNOS phosphorylation. MPA attenuated the E2-induced phosphorylation of Akt, a kinase that phosphorylates eNOS. Treatment with pure progesterone receptor (PR) antagonist RU486 completely abolished the inhibitory effect of MPA on E2-induced Akt phosphorylation and eNOS phosphorylation. In addition, the effects of actinomycin D were tested to rule out the influence of genomic events mediated by nuclear PRs. Actinomycin D did not affect the inhibitory effect of MPA on E2-induced Akt phosphorylation. Furthermore, the potential roles of PRA and PRB were evaluated. In COS cells transfected with either PRA or PRB, MPA attenuated E2-induced Akt phosphorylation. These results indicate that MPA attenuated E2-induced NO production via an Akt cascade through PRA or PRB in a non-genomic manner

  19. Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors

    Czech Academy of Sciences Publication Activity Database

    Ezechiáš, Martin; Janochová, Jana; Filipová, Alena; Křesinová, Zdena; Cajthaml, Tomáš

    2016-01-01

    Roč. 152, JUNE (2016), s. 284-291 ISSN 0045-6535 R&D Projects: GA TA ČR TE01020218; GA ČR GA13-28283S Institutional support: RVO:61388971 Keywords : Endocrine disruptor * Anti-estrogenic * Anti-androgenic Subject RIV: EE - Microbiology, Virology Impact factor: 4.208, year: 2016

  20. Estrogenic activity of estradiol and its metabolites in the ER-CALUX assay with human T47D breast cells

    NARCIS (Netherlands)

    Hoogenboom, L.A.P.; Haan, de L.; Hooijerink, D.; Bor, G.; Murk, A.J.; Brouwer, A.

    2001-01-01

    A number of metabolites of 17β-estradiol were tested for their estrogenic activity using the ER-CA-LUX assay based on the increased expression of luciferase in exposed T47D breast cancer cells. E2β and estrone showed similar potencies in the test, whereas E2α was 100 times less active. Incubation of

  1. PHENYLALANINE90 AND PHENYLALANINE93 ARE CRUCIAL AMINO ACIDS WITHIN THE ESTROGEN BINDING SITE OF THE HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A10

    OpenAIRE

    Starlard-Davenport, Athena; Xiong, Yan; Bratton, Stacie; Gallus-Zawada, Anna; Finel, Moshe; Radominska-Pandya, Anna

    2006-01-01

    Human UDP-glucuronosyltransferase 1A10 has been identified as the major isoform involved in the biotransformation of a wide range of phenolic substrates, including native estrogens and their oxidized metabolites. Our recent studies point to the F90-M91-V92-F93 amino acid motif of UGT1A10, which was identified using photoaffinity labeling followed by LC-MS/MS analysis, as a key determinant of the binding of phenolic substrates. In this report, we have evaluated the role of F90, V92, and F93 in...

  2. Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation

    International Nuclear Information System (INIS)

    Moerkens, Marja; Zhang, Yinghui; Wester, Lynn; Water, Bob van de; Meerman, John HN

    2014-01-01

    Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER) α -positive breast cancer patients. Although the mechanisms behind tamoxifen resistance are still not completely understood, clinical data suggests that increased expression of receptor tyrosine kinases is involved. Here, we studied the estrogen and anti-estrogen sensitivity of human breast cancer MCF7 cells that have a moderate, retroviral-mediated, ectopic expression of epidermal growth factor receptor (MCF7-EGFR). Proliferation of MCF7-EGFR and parental cells was induced by 17β-estradiol (E2), epidermal growth factor (EGF) or a combination of these. Inhibition of proliferation under these conditions was investigated with 4-hydroxy-tamoxifen (TAM) or fulvestrant at 10 -12 to 10 -6 M. Cells were lysed at different time points to determine the phosphorylation status of EGFR, MAPK 1/3 , AKT and the expression of ERα. Knockdown of target genes was established using smartpool siRNAs. Transcriptomics analysis was done 6 hr after stimulation with growth factors using Affymetrix HG-U133 PM array plates. While proliferation of parental MCF7 cells could only be induced by E2, proliferation of MCF7-EGFR cells could be induced by either E2 or EGF. Treatment with TAM or fulvestrant did significantly inhibit proliferation of MCF7-EGFR cells stimulated with E2 alone. EGF treatment of E2/TAM treated cells led to a marked cell proliferation thereby overruling the anti-estrogen-mediated inhibition of cell proliferation. Under these conditions, TAM however did still inhibit ERα- mediated transcription. While siRNA-mediated knock-down of EGFR inhibited the EGF- driven proliferation under TAM/E2/EGF condition, knock down of ERα did not. The TAM resistant cell proliferation mediated by the conditional EGFR-signaling may be dependent on the PI3K/Akt pathway but not the MEK/MAPK pathway, since a MEK inhibitor (U0126), did not block the proliferation. Transcriptomic analysis under the various E2/TAM

  3. Growth kinetics of four human breast carcinomas grown in nude mice

    DEFF Research Database (Denmark)

    Spang-Thomsen, M; Rygaard, K; Hansen, L

    1989-01-01

    The immune-deficient nude mouse with human tumor xenografts is an appropriate model system for performing detailed growth kinetic examinations. In the present study one estrogen and progesterone receptor-negative (T60) and three receptor-positive (Br-10, MCF-7, T61) human breast cancer xenografts...... in nude mice were investigated. The proliferative tumor characteristics were examined by growth curves, thymidine labelling technique, and flow cytometric DNA analysis performed on fine-needle aspirations. The results showed that the tumors had growth kinetics comparable to other human tumor types...

  4. Kaempferol targets estrogen-related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions.

    Science.gov (United States)

    Wu, Yan; Zhang, Qinmei; Zhang, Rui

    2017-12-01

    Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of new-onset blindness in the developed world. The present study aimed to examine the effect of kaempferol on high glucose-induced human retinal endothelial cells (HRECs) in vitro . The expression levels of various mRNAs and proteins were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. The target of kaempferol was determined using a luciferase reporter assay. In addition, HREC proliferation, migration and cell sprouting were determined using Cell Counting kit-8, wound scratch and tube formation assays, respectively. RT-qPCR and western blotting results showed that treatment with 30 mM glucose for 12, 24 and 48 h increased the expression level of estrogen-related receptor α (ERRα) mRNA and protein. The luciferase reporter assay demonstrated that kaempferol inhibited ERRα activity in HRECs. Compared with 5 mM normal glucose treatment, high (30 mM) glucose significantly promoted the proliferation, migration and tube formation of HRECs, which was antagonized by 10 and 30 µM kaempferol in a dose-dependent manner. Treatment with 30 mM glucose also increased the expression of vascular endothelial growth factor (VEGF) mRNA and protein, and the expression levels of VEGF mRNA and protein were suppressed by kaempferol (10 and 30 µM). Kaempferol (30 µM) treatment also increased the expression levels of thrombospondin 1 (TSP-1) and a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS-1) mRNA; however, TSP-1 and ADAMTS-1 levels did not differ between high glucose and normal (5 mM) glucose conditions. The results of this study suggest that kaempferol targets ERRα and suppresses the angiogenesis of HRECs under high glucose conditions. Kaempferol may be a potential drug for use in controlling the progression of DR; however, in vivo studies are required to evaluate its efficacy and safety.

  5. ERα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene BRMS1

    Directory of Open Access Journals (Sweden)

    Hongtao Ma

    2016-01-01

    Full Text Available Recently, estrogen has been reported as putatively inhibiting cancer cell invasion and motility. This information is in direct contrast to the paradigm of estrogen as a tumor promoter. However, data suggests that the effects of estrogen are modulated by the receptor isoform with which it interacts. In order to gain a clearer understanding of the role of estrogen in potentially suppressing breast cancer metastasis, we investigated the regulation of estrogen and its receptor on the downstream target gene, breast cancer metastasis suppressor 1 (BRMS1 in MCF-7, SKBR3, TTU-1 and MDA-MB-231 breast cancer cells. Our results showed that estrogen increased the transcription and expression of BRMS1 in the ERα positive breast cancer cell line, MCF-7. Additionally, the ERα specific agonist PPT also induced the transcription and expression of BRMS1. However, the two remaining estrogen receptor (ER subtype agonists had no effect on BRMS1 expression. In order to further examine the influence of ERα on BRMS1 expression, ERα expression was knocked down using siRNA (siERα. Western blot analysis showed that siERα reduced estrogen-induced and PPT-induced BRMS1 expression. In summary, this study demonstrates estrogen, via its α receptor, positively regulates the expression of BRMS1, providing new insight into a potential inhibitory effect of estrogen on metastasis suppression.

  6. Estrogen, Estrogen Receptor and Lung Cancer

    Directory of Open Access Journals (Sweden)

    Li-Han Hsu

    2017-08-01

    Full Text Available Estrogen has been postulated as a contributor for lung cancer development and progression. We reviewed the current knowledge about the expression and prognostic implications of the estrogen receptors (ER in lung cancer, the effect and signaling pathway of estrogen on lung cancer, the hormone replacement therapy and lung cancer risk and survival, the mechanistic relationship between the ER and the epidermal growth factor receptor (EGFR, and the relevant clinical trials combining the ER antagonist and the EGFR antagonist, to investigate the role of estrogen in lung cancer. Estrogen and its receptor have the potential to become a prognosticator and a therapeutic target in lung cancer. On the other hand, tobacco smoking aggravates the effect of estrogen and endocrine disruptive chemicals from the environment targeting ER may well contribute to the lung carcinogenesis. They have gradually become important issues in the course of preventive medicine.

  7. [18F]-fluorodeoxyglucose positron emission tomography can contribute to discriminate patients with poor prognosis in hormone receptor-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Sung Gwe Ahn

    Full Text Available Patients with hormone receptor-positive breast cancer typically show favorable survival. However, identifying individuals at high risk of recurrence among these patients is a crucial issue. We tested the hypothesis that [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET scans can help predict prognosis in patients with hormone receptor-positive breast cancer.Between April 2004 and December 2008, 305 patients with hormone receptor-positive breast cancer who underwent FGD-PET were enrolled. Patients with luminal B subtype were identified by positivity for human epidermal growth factor receptor-2 (HER2 or high Ki67 (≥14% according to criteria recently recommended by the St. Gallen panelists. The cut-off value of SUVmax was defined using the time-dependent receiver operator characteristic curve for recurrence-free survival (RFS.At a median follow up of 6.23 years, continuous SUVmax was a significant prognostic factor with a hazard ratio (HR of 1.21 (p = 0.021. The cut-off value of SUVmax was defined as 4. Patients with luminal B subtype (n = 82 or high SUVmax (n = 107 showed a reduced RFS (p = 0.031 and 0.002, respectively. In multivariate analysis for RFS, SUVmax carried independent prognostic significance (p = 0.012 whereas classification with immunohistochemical markers did not (p = 0.274. The Harell c-index was 0.729. High SUVmax was significantly associated with larger tumor size, positive nodes, HER2 positivity, high Ki67 (≥14%, high tumor grade, and luminal B subtype.Among patients with hormone receptor-positive breast cancer, FDG-PET can help discriminate patients at high risk of tumor relapse.

  8. Do estrogenic compounds in drinking water migrating from plastic pipe distribution system pose adverse effects to human? An analysis of scientific literature.

    Science.gov (United States)

    Liu, Ze-Hua; Yin, Hua; Dang, Zhi

    2017-01-01

    With the widespread application of plastic pipes in drinking water distribution system, the effects of various leachable organic chemicals have been investigated and their occurrence in drinking water supplies is monitored. Most studies focus on the odor problems these substances may cause. This study investigates the potential endocrine disrupting effects of the migrating compound 2,4-di-tert-butylphenol (2,4-d-t-BP). The summarized results show that the migration of 2,4-d-t-BP from plastic pipes could result in chronic exposure and the migration levels varied greatly among different plastic pipe materials and manufacturing brands. Based on estrogen equivalent (EEQ), the migrating levels of the leachable compound 2,4-d-t-BP in most plastic pipes were relative low. However, the EEQ levels in drinking water migrating from four out of 15 pipes may pose significant adverse effects. With the increasingly strict requirements on regulation of drinking water quality, these results indicate that some drinking water transported with plastic pipes may not be safe for human consumption due to the occurrence of 2,4-d-t-BP. Moreover, 2,4-d-t-BP is not the only plastic pipe-migrating estrogenic compound, other compounds such as 2-tert-butylphenol (2-t-BP), 4-tert-butylphenol (4-t-BP), and others may also be leachable from plastic pipes.

  9. Estrogens and aging skin

    OpenAIRE

    Thornton, M. Julie

    2013-01-01

    Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity...

  10. Effects of estrogen on the vascular system

    Directory of Open Access Journals (Sweden)

    R.C. Tostes

    2003-09-01

    Full Text Available The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall. Estrogen is active both on vascular smooth muscle and endothelial cells where functionally competent estrogen receptors have been identified. Estrogen administration promotes vasodilation in humans and in experimental animals, in part by stimulating prostacyclin and nitric oxide synthesis, as well as by decreasing the production of vasoconstrictor agents such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1. In vitro, estrogen exerts a direct inhibitory effect on smooth muscle by activating potassium efflux and by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, 17ß-estradiol prevents neointimal thickening after balloon injury and also ameliorates the lesions occurring in atherosclerotic conditions. As is the case for other steroids, the effect of estrogen on the vessel wall has a rapid non-genomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression.

  11. EADB: An Estrogenic Activity Database for Assessing ...

    Science.gov (United States)

    Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body’s endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/ BioinformaticsTools/EstrogenicActivityDatabaseEADB/default. htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of

  12. Estrogen and its role in gastrointestinal health and disease.

    LENUS (Irish Health Repository)

    Hogan, Aisling M

    2012-02-01

    INTRODUCTION: While the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes. METHODS: A literature search was conducted using the PubMed database and the search terms were "estrogen," "estrogen AND gastrointestinal tract," "estrogen AND colon," "estrogen AND esophagus," "estrogen AND small intestine," "estrogen AND stomach," "estrogen AND gallbladder," and "estrogen AND motility." Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis. CONCLUSIONS: Effects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

  13. Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: Role of transcription factors

    Energy Technology Data Exchange (ETDEWEB)

    Chandrasekharan, Sabarinath, E-mail: csab@bio.psgtech.ac.in [Department of Biotechnology, PSG College of Technology, Coimbatore 641004 (India); Kandasamy, Krishna Kumar [Max Planck Institute for Biology of Ageing, Cologne (Germany); Dayalan, Pavithra; Ramamurthy, Viraragavan [Department of Biotechnology, PSG College of Technology, Coimbatore 641004 (India)

    2013-08-02

    Highlights: •Estradiol (E2) at low dose induced cell proliferation in breast cancer cells. •E2 at high concentration induced cell stress in breast cancer cells. •Estrogen receptor physically interacts only with a few transcription factors. •Differential expression of genes with Oct-1 binding sites increased under stress. •Transcription factor binding sites showed distinct spatial distribution on genes. -- Abstract: Background: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet. Methodology: Meta-analysis of the expression data of MCF7 cells treated with low (1 nM) or high (100 nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25 kb upstream and downstream from the transcription start site (TSS) of these genes. Results: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes. Discussion: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress–rescue responses were induced

  14. Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: Role of transcription factors

    International Nuclear Information System (INIS)

    Chandrasekharan, Sabarinath; Kandasamy, Krishna Kumar; Dayalan, Pavithra; Ramamurthy, Viraragavan

    2013-01-01

    Highlights: •Estradiol (E2) at low dose induced cell proliferation in breast cancer cells. •E2 at high concentration induced cell stress in breast cancer cells. •Estrogen receptor physically interacts only with a few transcription factors. •Differential expression of genes with Oct-1 binding sites increased under stress. •Transcription factor binding sites showed distinct spatial distribution on genes. -- Abstract: Background: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet. Methodology: Meta-analysis of the expression data of MCF7 cells treated with low (1 nM) or high (100 nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25 kb upstream and downstream from the transcription start site (TSS) of these genes. Results: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes. Discussion: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress–rescue responses were induced

  15. Affinity of estrogens for human progesterone receptor A and B monomers and risk of breast cancer: a comparative molecular modeling study

    Directory of Open Access Journals (Sweden)

    Tarique N Hasan

    2011-03-01

    Full Text Available Tarique N Hasan1,4, Leena Grace B2, Tariq A Masoodi3,5, Gowhar Shafi4 , Ali A. Alshatwi4, P Sivashanmugham31Department of Biotechnology, Bharathiar University, Coimbator, TN, India; 2Department of Biotechnology, V. M. K. V. College of Engineering, Salem, TN, India; 3Department of Bioinformatics, Jamal Mohammed College, Bharathidasan University, Tiruchirappalli, India; 4Molecular Cancer Biology Laboratory, Department of Food Science and Nutrition, College of Food and Agricultural Sciences; 5Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Saudi ArabiaBackground: The human progesterone receptor (hPR belongs to the steroid receptor family. It may be found as monomers (A and B and or as a dimer (AB. hPR is regarded as the prognostic biomarker for breast cancer. In a cellular dimer system, AB is the dominant species in most cases. However, when a cell coexpresses all three isoforms of hPR, the complexity of the action of this receptor increases. For example, hPR A suppresses the activity of hPR B, and the ratio of hPR A to hPR B may determine the physiology of a breast tumor. Also, persistent exposure of hPRs to nonendogenous ligands is a common risk factor for breast cancer. Hence we aimed to study progesterone and some nonendogenous ligand interactions with hPRs and their molecular docking.Methods and results: A pool of steroid derivatives, namely, progesterone, cholesterol, testosterone, testolectone, estradiol, estrone, norethindrone, exemestane, and norgestrel, was used for this in silico study. Dockings were performed on AutoDock 4.2. We found that estrogens, including estradiol and estrone, had a higher affinity for hPR A and B monomers in comparison with the dimer, hPR AB, and that of the endogenous progesterone ligand. hPR A had a higher affinity to all the docked ligands than hPR B.Conclusion: This study suggests that the exposure of estrogens to hPR A as well as hPR B, and more

  16. Enzyme-immuno assay for total estrogens and human placental lactogen. Comparison with radio-immuno-assay in normal pregnancy-monitoring

    International Nuclear Information System (INIS)

    Raichvarg, D.; Tallet, F.; Lajeunie, E.; Bonnaire, Y.; Danglas, P.

    1980-01-01

    The concentrations of estrogens (E) and human placental lactogen (HLP) are estimated in sera by radio immuno-assay (RIA) and enzyme-immuno-assay (EIA). Statistical data indicate mean intra-assay variation coefficients of 7% and 12% for E and HLP tests, respectively. The correlation coefficient (RIA/EIA) are found higher than 0,9% for both hormonal assays. The dilution curves obtained by RIA and EIA are similar. However, Student'test gives a significant difference for E determination. In fact, total E and E 3 only are measured by EIA and RIA, respectively. In most cases biological interferences are negligible except for HLP in presence of higher protein or haemoglobin levels. RIA and EIA are performed to study serum HLP and E levels throughout normal pregnancies. Results allow to use EIA for HLP and E evaluations in pregnancy-monitoring [fr

  17. Rapid insulinotropic action of low doses of bisphenol-A on mouse and human islets of Langerhans: role of estrogen receptor β.

    Directory of Open Access Journals (Sweden)

    Sergi Soriano

    Full Text Available Bisphenol-A (BPA is a widespread endocrine-disrupting chemical (EDC used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ-/- mice to study whether ERβ is involved in the rapid regulation of K(ATP channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM. We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased K(ATP channel activity, increased glucose-induced [Ca(2+](i signals and insulin release in β-cells from WT mice but not in cells from ERβ-/- mice. The rapid reduction in the K(ATP channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

  18. Modeling mixtures of environmental estrogens found in U.S. surface waters with an in vitro estrogen mediated transcriptionai activation assay (T47D-KBluc).

    Science.gov (United States)

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. Environmental estrogens can come from various sources including concentrated animal feedlot operations (CAFO), municipa...

  19. G protein-coupled estrogen receptor 1 (GPER, GPR 30) in normal human endometrium and early pregnancy decidua.

    Science.gov (United States)

    Kolkova, Z; Noskova, V; Ehinger, A; Hansson, S; Casslén, B

    2010-10-01

    The recently identified trans-membrane G protein-coupled estrogen receptor 1 (GPER, GPR30) has been implicated in rapid non-genomic effects of estrogens. This focuses on expression and localization of GPER mRNA and protein in normal cyclic endometrium and early pregnancy decidua. Real-time PCR, western blotting, in situ hybridization and immuno-histochemistry were used. Endometrial expression of GPER mRNA was lower in the secretory phase than in the proliferative phase, and even lower in the decidua. The expression pattern was similar to that of ERα mRNA, but different from that of ERβ mRNA. Western blot detected GPER protein as a 54 kDa band in all endometrial and decidual samples. In contrast to the mRNA, GPER protein did not show cyclic variations. Apparently, a lower amount of mRNA is sufficient to maintain protein levels in the secretory phase. GPER mRNA was predominantly localized in the epithelium of mid- and late-proliferative phase endometrium, whereas expression in early proliferative and secretory glands could not be distinguished from the diffuse stromal signal, which was present throughout the cycle. Immuno-staining for GPER was stronger in glandular and luminal epithelium than in the stroma throughout the cycle. The cyclic variations of GPER mRNA obviously relate to strong epithelial expression in the proliferative phase, and the expression pattern suggests regulation by ovarian steroids. GPER protein is present in endometrial tissue throughout the cycle, and the epithelial localization suggests potential functions during sperm migration at mid-cycle, as well as decidualization and blastocyst implantation in the mid-secretory phase.

  20. 17β-Estradiol-induced interaction of estrogen receptor α and human atrial essential myosin light chain modulates cardiac contractile function.

    Science.gov (United States)

    Duft, Karolin; Schanz, Miriam; Pham, Hang; Abdelwahab, Ahmed; Schriever, Cindy; Kararigas, Georgios; Dworatzek, Elke; Davidson, Mercy M; Regitz-Zagrosek, Vera; Morano, Ingo; Mahmoodzadeh, Shokoufeh

    2017-01-01

    Chronic increased workload of the human heart causes ventricular hypertrophy, re-expression of the atrial essential myosin light chain (hALC-1), and improved contractile function. Although hALC-1 is an important positive inotropic regulator of the human heart, little is known about its regulation. Therefore, we investigated the role of the sex hormone 17β-estradiol (E2) on hALC-1 gene expression, the underlying molecular mechanisms, and the impact of this regulatory process on cardiac contractile function. We showed that E2 attenuated hALC-1 expression in human atrial tissues of both sexes and in human ventricular AC16 cells. E2 induced the nuclear translocation of estrogen receptor alpha (ERα) and hALC-1 in AC16 cells, where they cooperatively regulate the transcriptional activity of hALC-1 gene promoter. E2-activated ERα required the estrogen response element (ERE) motif within the hALC-1 gene promoter to reduce its transcriptional activity (vehicle: 15.55 ± 4.80 vs. E2: 6.51 ± 3.69; ~2 fold). This inhibitory effect was potentiated in the presence of hALC-1 (vehicle: 11.13 ± 3.66 vs. E2: 2.18 ± 1.10; ~5 fold), and thus, hALC-1 acts as a co-repressor of ERα-mediated transcription. Yeast two-hybrid screening of a human heart cDNA library revealed that ERα interacts physically with hALC-1 in the presence of E2. This interaction was confirmed by Co-Immunoprecipitation and immunofluorescence in human atrium. As a further novel effect, we showed that chronic E2-treatment of adult mouse cardiomyocytes overexpressing hALC-1 resulted in reduced cell-shortening amplitude and twitching kinetics of these cells independent of Ca 2+ activation levels. Together, our data showed that the expression of hALC-1 gene is, at least partly, regulated by E2/ERα, while hALC-1 acts as a co-repressor. The inotropic effect of hALC-1 overexpression in cardiomyocytes can be significantly repressed by E2.

  1. ERα36, a variant of estrogen receptor α, is predominantly localized in mitochondria of human uterine smooth muscle and leiomyoma cells.

    Directory of Open Access Journals (Sweden)

    Yitang Yan

    Full Text Available ERα36 is a naturally occurring, membrane-associated, isoform of estrogen receptor α. The expression of ERα36 is due to alternative splicing and different promoter usage. ERα36 is a dominant-negative effector of ERα66-mediated transactivational activities and has the potential to trigger membrane-initiated mitogenic, nongenomic, estrogen signaling; however, the subcellular localization of ERα36 remains controversial. To determine the cellular localization of ERα36 in estrogen-responsive human uterine smooth muscle (ht-UtSMC and leiomyoma (fibroid; ht-UtLM cells, we conducted systematic confocal microscopy and subcellular fractionation analysis using ERα36 antibodies. With Image J colocalizaton analysis plugin, confocal images were analyzed to obtain a Pearson's Correlation Coefficient (PCC to quantify signal colocalization of ERα36 with mitochondrial, endoplasmic reticulum, and cytoskeletal components in both cell lines. When cells were double-stained with an ERα36 antibody and a mitochondrial-specific dye, MitoTracker, the PCC for the two channel signals were both greater than 0.75, indicating strong correlation between ERα36 and mitochondrial signals in the two cell lines. A blocking peptide competition assay confirmed that the mitochondria-associated ERα36 signal detected by confocal analysis was specific for ERα36. In contrast, confocal images double-stained with an ERα36 antibody and endoplasmic reticulum or cytoskeletal markers, had PCCs that were all less than 0.4, indicating no or very weak signal correlation. Fractionation studies showed that ERα36 existed predominantly in membrane fractions, with minimal or undetected amounts in the cytosol, nuclear, chromatin, and cytoskeletal fractions. With isolated mitochondrial preparations, we confirmed that a known mitochondrial protein, prohibitin, was present in mitochondria, and by co-immunoprecipitation analysis that ERα36 was associated with prohibitin in ht-UtLM cells. The

  2. Identification of an estrogenic hormone receptor in Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Mimoto, Ai; Fujii, Madoka; Usami, Makoto; Shimamura, Maki; Hirabayashi, Naoko; Kaneko, Takako; Sasagawa, Noboru; Ishiura, Shoichi

    2007-01-01

    Changes in both behavior and gene expression occur in Caenorhabditis elegans following exposure to sex hormones such as estrogen and progesterone, and to bisphenol A (BPA), an estrogenic endocrine-disrupting compound. However, only one steroid hormone receptor has been identified. Of the 284 known nuclear hormone receptors (NHRs) in C. elegans, we selected nhr-14, nhr-69, and nhr-121 for analysis as potential estrogenic hormone receptors, because they share sequence similarity with the human estrogen receptor. First, the genes were cloned and expressed in Escherichia coli, and then the affinity of each protein for estrogen was determined using a surface plasmon resonance (SPR) biosensor. All three NHRs bound estrogen in a dose-dependent fashion. To evaluate the specificity of the binding, we performed a solution competition assay using an SPR biosensor. According to our results, only NHR-14 was able to interact with estrogen. Therefore, we next examined whether nhr-14 regulates estrogen signaling in vivo. To investigate whether these interactions actually control the response of C. elegans to hormones, we investigated the expression of vitellogenin, an estrogen responsive gene, in an nhr-14 mutant. Semi-quantitative RT-PCR showed that vitellogenin expression was significantly reduced in the mutant. This suggests that NHR-14 is a C. elegans estrogenic hormone receptor and that it controls gene expression in response to estrogen

  3. Morphologic transformation of human breast epithelial cells MCF-10A: dependence on an oxidative microenvironment and estrogen/epidermal growth factor receptors

    Directory of Open Access Journals (Sweden)

    Yusuf Rita

    2010-09-01

    Full Text Available Abstract Background MCF-10A, immortalized but non-transformed human breast epithelial cells, are widely used in research examining carcinogenesis. The studies presented here were initiated with the observation that MCF-10A cells left in continuous culture for prolonged periods without re-feeding were prone to the development of transformed foci. We hypothesized that the depletion of labile culture components led to the onset of processes culminating in the observed cell transformation. The purpose of this study was to define the factors which promoted transformation of this cell line. Results Changes in levels of phenol red (PHR, hydrocortisone (HC, and epidermal growth factor (EGF with or without estrogen treatment indicated that both oxidative stress- and estrogen receptor alpha (ERα-mediated pathways contribute to cell transformation. Gene array and Western blotting analyses of cells maintained in our laboratory and of those from other sources documented detectable ERα and ERbeta (ERβ in this ERα-negative cataloged cell line. Results also indicate the possibility of a direct association of EGF receptor (EGFR and ERα in these cells as well as the formation and high induction of a novel ternary complex that includes ERβ (ERα/ERβ/EGFR in cells grown under conditions facilitating transformation. Conclusions Our studies resulted in the development of a growth protocol where the effects of chronic, physiologically relevant alterations in the microenvironment on cellular transformation were examined. From our results, we were able to propose a model of transformation within the MCF-10A cell line in which oxidative stress, ER and EGFR play essential roles. Overall, our work indicates that the immediate microenvironment of cells exerts powerful growth cues which ultimately determine their transformation potential.

  4. Effects of Titanium Surface Microtopography and Simvastatin on Growth and Osteogenic Differentiation of Human Mesenchymal Stem Cells in Estrogen-Deprived Cell Culture.

    Science.gov (United States)

    Arpornmaeklong, Premjit; Pripatnanont, Prisana; Chookiatsiri, Chonticha; Tangtrakulwanich, Boonsin

    This study aimed to investigate the effects of titanium surface topography and simvastatin on growth and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) in estrogen-deprived (ED) cell culture. Human BMSCs were seeded on cell culture plates, smooth-surface titanium (Ti) disks, and sandblasted with large grits and acid etched (SLA)-surface Ti disks; and subsequently cultured in regular (fetal bovine serum [FBS]), ED, and ED-with 100 nM simvastatin (ED-SIM) culture media for 14 to 21 days. Live/dead cell staining, scanning electron microscope examination, and cell viability assay were performed to determine cell attachment, morphology, and growth. Expression levels of osteoblast-associated genes, Runx2 and bone sialoprotein and levels of alkaline phosphatase (ALP) activity, calcium content, and osteocalcin in culture media were measured to determine osteoblastic differentiation. Expression levels of bone morphogenetic protein-2 (BMP-2) were investigated to examine stimulating effects of simvastatin (n = 4 to 5, mean ± SD). In vitro mineralization was verified by calcein staining. Human BMSCs exhibited different attachment and shapes on smooth and SLA titanium surfaces. Estrogen-deprived cell culture decreased cell attachment and growth, particularly on the SLA titanium surface, but cells were able to grow to reach confluence on day 21 in the ED-osteogenic (OS) culture medium. Promoting effects of the SLA titanium surface in ED-OS were significantly decreased. Simvastatin significantly increased osteogenic differentiation of human BMSCs on the SLA titanium surface in the ED-OS medium, and the promoting effects of simvastatin corresponded with the increasing of BMP-2 gene expression on the SLA titanium surface in ED-OS-SIM culture medium. The ED cell culture model provided a well-defined platform for investigating the effects of hormones and growth factors on cells and titanium surface interaction. Titanium, the SLA surface, and simvastatin

  5. The Z-isomer of 11β-methoxy-17α-[123I]iodovinylestradiol is a promising radioligand for estrogen receptor imaging in human breast cancer

    International Nuclear Information System (INIS)

    Rijks, Leonie J. M.; Boer, Gerard J.; Endert, Erik; Bruin, Kora de; Janssen, Anton G. M.; Royen, Eric A. van

    1997-01-01

    The potential of both stereoisomers of 11β-methoxy-17α-[ 123 I]iodovinylestradiol (E- and Z-[ 123 I]MIVE) as suitable radioligands for imaging of estrogen receptor(ER)-positive human breast tumours was studied. The 17α-[ 123 I]iodovinylestradiol derivatives were prepared stereospecifically by oxidative radioiododestannylation of the corresponding 17α-tri-n-butylstannylvinylestradiol precursors. Both isomers of MIVE showed high in vitro affinity for dimethylbenzanthracene-induced rat and fresh human mammary tumour ER, that of Z-MIVE however being manyfold higher than that of E-MIVE. In vivo distribution studies with E- and Z-[ 123 I]MIVE in normal and tumour-bearing female rats showed ER-mediated uptake and retention in uterus, ovaries, pituitary, hypothalamus and mammary tumours, again the highest for Z-[ 123 I]MIVE. The uterus- and tumour-to-nontarget tissue (fat, muscle) uptake ratios were also highest for Z-[ 123 I]MIVE. Additionally, planar whole body imaging of two breast cancer patients 1-2 h after injection of Z-[ 123 I]MIVE showed increased focal uptake at known tumour sites. Therefore, we conclude that Z-[ 123 I]MIVE is a promising radioligand for the diagnostic imaging of ER in human breast cancer

  6. Computational method for discovery of estrogen responsive genes

    DEFF Research Database (Denmark)

    Tang, Suisheng; Tan, Sin Lam; Ramadoss, Suresh Kumar

    2004-01-01

    of human genes are functionally well characterized. It is still unclear how many and which human genes respond to estrogen treatment. We propose a simple, economic, yet effective computational method to predict a subclass of estrogen responsive genes. Our method relies on the similarity of ERE frames...

  7. Estrogens in breast cancer

    International Nuclear Information System (INIS)

    Terzieff, V.; Vázquez, A.

    2004-01-01

    The prolonged exposure to estrogen increases the risk of cancer breast, the precise role of estrogen in the carcinogenesis process is unclear. They are capable of inducing cell proliferation through different channels receptor Estrogen (ER) known, for example through MAPkinasa sensitivity the promoter of proliferation effect depends on the level of RE, or type to â, integrity (mutations may alter its function) and ligand. The different types of estrogens and related compounds have different profile of affinity for RE and effect end. The modulatory role of progestogens proliferation is very complex, and the interaction between the effector pathways of progestin’s, estrogens, EGF and IGF family - maybe others - determines the final effect .. Estrogens are mutagenic per se weak, but is now known for its hepatic metabolism occur highly reactive species such as quinones, and catechol, powerful mutagens in vitro. Direct or indirect genotoxicity probably explains Part of the effects of estrogen on tumor cells. The use of hormone replacement (HTR) increases the risk of CM, as proportional to the time of use. The combination with progestin seems to be increased risk (R R 2). It is unclear the role of phyto estrogens in the prevention the CM. In the male breast is known that the proliferative response to parenchymal different hormonal maneuvers is different. The effect is minimal castration are and maximum with the combination of estrogen and progesterone. It is unclear, however, the risk of the population exposed to hormone therapy for cancer prostate or otherwise

  8. Risk of Recurrence or Contralateral Breast Cancer More than 5 Years After Diagnosis of Hormone Receptor-Positive Early-Stage Breast Cancer.

    Science.gov (United States)

    Wilson, Sheridan; Speers, Caroline; Tyldesley, Scott; Chia, Stephen; Kennecke, Hagen; Ellard, Susan; Lohrisch, Caroline

    2016-08-01

    Three large studies have shown a survival benefit from 10 years of adjuvant hormone therapy (AHT). We evaluated the risk of an event 5 years after the initial breast cancer (BC) diagnosis and identified the prognostic factors to assist clinicians considering extended AHT. Patients newly referred to the BC Cancer Agency with stage I to III estrogen receptor-positive BC diagnosed from 1989 to 2004 who had undergone AHT were identified by the BC Cancer Agency's Breast Cancer Outcomes Unit. Cases with recurrence, death, or contralateral BC occurring within the first 5 years were excluded. The 10-year event-free survival (EFS) and 95% confidence intervals (CIs) were calculated using the Kaplan-Meier method. This provided estimates of recurrence risk after the fifth year following the diagnosis. The histopathologic and age variables were examined for prognostic value by univariate analysis. Within our cohort, 6615 women were postmenopausal and 1886 were premenopausal at the BC diagnosis. The median follow-up period was 11 years. The 10-year EFS for women aged cancer (any grade) and for stage II (node-negative and node-positive), grade I cancer. Our data have identified BCs associated with a very low recurrence risk 5 to 10 years after diagnosis, providing women with such cancers confidence about a decision to discontinue AHT after 5 years. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Synthesis and characterisation of [90Y]-Bz-DTPA-oct: a yttrium-90-labelled octreotide analogue for radiotherapy of somatostatin receptor-positive tumours

    International Nuclear Information System (INIS)

    Smith-Jones, Peter M.; Stolz, Barbara; Albert, Rainer; Ruser, Gerd; Briner, Ulrich; Maecke, Helmut R.; Bruns, Christian

    1998-01-01

    An investigation into the in vitro behaviour of two yttrium-90-labelled somatostatin analogues was performed. Further in vivo characterisation was performed with the most promising agent. A new DTPA-octreotide analogue (Bz-DTPA-oct) was synthesised by coupling a bifunctional DTPA chelator to the N-terminal amine of the D-Phe 1 of Tyr 3 -octreotide. This new SRIF analogue and DTPA-octreotide (OctreoScan) were radiolabelled with 90 Y prior to serum stability being evaluated. Receptor binding assays were also performed on the two radioligands using rat cortex membranes. The [ 90 Y]-Bz-DTPA-oct was further evaluated in vivo using tumour-bearing rats. The first conjugate (DTPA-octreotide) bound with a high affinity to SRIF receptors and the 90 Y complex was relatively stable in human serum (t 1/2 3.8 d for 90 Y lost to serum proteins). The second conjugate (Bz-DTPA-oct) also exhibited a high binding affinity to SRIF receptors, but it demonstrated an even slower loss of 90 Y to serum proteins (t 1/2 12.1 d). The in vivo evaluation of the more stable [ 90 Y]-Bz-DTPA-oct showed a very rapid and high accumulation in somatostatin receptor-positive tumours, which after 1 h resulted in tumour/nontumour ratios of 3.8, 21, and 4.9 (for blood, muscle, and liver, respectively). These tumour/nontumour ratios increased, and were by 24 h postinjection 138, 285, and 6.1 (for blood, muscle, and liver). Yttrium-90-labelled Bz-DTPa-oct is rapidly and selectively accumulated in somatostatin receptor-positive tissue. Octadentate Bz-DTPA-oct could be ligand for 90 Y radiotherapy of somatostatin receptor-positive tumours and their metastases

  10. Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats.

    Science.gov (United States)

    Vlachou, Styliani; Guery, Sebastien; Froestl, Wolfgang; Banerjee, Deboshri; Benedict, Jessica; Finn, M G; Markou, Athina

    2011-05-01

    γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA(B) receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA(B) receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA(B) receptor agonists, GABA(B) receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. We examined whether the acute effects of the GABA(B) receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self-administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. These results showed that BHF177 selectively blocked nicotine self-administration and prevented cue-induced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA(B) receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans.

  11. Isolation of the human anionic glutathione S-transferase cDNA and the relation of its gene expression to estrogen-receptor content in primary breast cancer

    International Nuclear Information System (INIS)

    Moscow, J.A.; Townsend, A.J.; Goldsmith, M.E.; Whang-Peng, J.; Vickers, P.J.; Poisson, R.; Legault-Poisson, S.; Myers, C.E.; Cowan, K.H.

    1988-01-01

    The development of multidrug resistance in MCF7 human breast cancer cells is associated with overexpression of P-glycoprotein, changes in activities of several detoxication enzymes, and loss of hormone sensitivity and estrogen receptors (ERs). The authors have cloned the cDNA for one of the drug-detoxifying enzymes overexpressed in multidrug-resistant MCF7 cells (Adr R MCF7), the anionic isozyme of glutathione S-transferase (GSTπ). Hybridization with this GSTπ cDNA, GSTπ-1, demonstrated that increased GSTπ activity in Adr R MCF7 cells is associated with overexpression but not with amplification of the gene. They mapped the GSTπ gene to human chromosome 11q13 by in situ hybridization. Since multidrug resistance and GSTπ overexpression are associated with the loss of ERs in Adr R MCF7 cells, they examined several other breast cancer cell lines that were not selected for drug resistance. In each of these cell lines they found an inverse association between GSTπ expression and ER content. They also examined RNA from 21 primary breast cancers and found a similar association between GSTπ expression and ER content in vivo. The finding of similar patterns of expression of a drug-detoxifying enzyme and of ERs in vitro as well as in vivo suggests that ER-negative breast cancer cells may have greater protection against antineoplastic agents conferred by GSTπ than ER-positive tumors

  12. Human Adrenal Androgens: Regulation of Biosynthesis and Role in Estrogen-Responsive Breast Cancer in a Mouse Model

    National Research Council Canada - National Science Library

    Hornsby, Peter

    1997-01-01

    .... An androgen-dependent human breast cancer model was established in the scid mouse. To provide zona reticularis function, essential for adrenal androgen biosynthesis, in human adrenal organoids in the mouse, two approaches are being taken...

  13. Validation of a rapid yeast estrogen bioassay, based on the expression of green fluorescent protein, for the screening of estrogenic activity in calf urine

    NARCIS (Netherlands)

    Bovee, T.F.H.; Heskamp, H.H.; Hamers, A.R.M.; Hoogenboom, L.A.P.; Nielen, M.W.F.

    2005-01-01

    Previously we described the construction and properties of a rapid yeast bioassay stably expressing human estrogen receptor a (hERa) and yeast enhanced green fluorescent protein (yEGFP) in response to estrogens. In the present study, this yeast estrogen assay was validated as a qualitative screening

  14. Determining estrogenic activity in serum from ovariectomized rats treated with environmental compounds using an in vitro estrogen-mediated transcriptional activation assay (T47D-KBluc)

    Science.gov (United States)

    The use of cell-based assays to quantify low levels of estrogen in human serum is an accepted method. These assays are more sensitive but less specific than radioimmunoassays (RIA). Thus, we hypothesized that estrogen responsive T47D-KBluc cells would detect estrogenic activity i...

  15. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jiajia [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Yuan, Yun [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Lu, Danfeng; Du, Baowen [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Xiong, Liang; Shi, Jiangong [State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Yang, Lijuan [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Liu, Wanli [MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Yuan, Xiaohong [School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Zhang, Guolin, E-mail: zhanggl@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China); Wang, Fei, E-mail: wangfei@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China)

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC{sub 50}: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They

  16. Molecular Docking and 3D-Pharmacophore Modeling to Study the Interactions of Chalcone Derivatives with Estrogen Receptor Alpha

    Directory of Open Access Journals (Sweden)

    Muchtaridi Muchtaridi

    2017-10-01

    Full Text Available Tamoxifen is the most frequently used anti-estrogen adjuvant treatment for estrogen receptor-positive breast cancer. However, it is associated with an increased risk of several serious side–effects, such as uterine cancer, stroke, and pulmonary embolism. The 2′,4′-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA from plant leaves of Eugenia aquea, has been found to inhibit the proliferation of MCF-7 human breast cancer cells in a dose-dependent manner, with an IC50 of 74.5 μg/mL (250 μM. The aim of this work was to study the molecular interactions of new ChalcEA derivatives formed with the Estrogen Receptor α (ERα using computer aided drug design approaches. Molecular docking using Autodock 4.2 was employed to explore the modes of binding of ChalcEA derivatives with ERα. The 3D structure-based pharmacophore model was derived using LigandScout 4.1 Advanced to investigate the important chemical interactions of the ERα-tamoxifen complex structure. The binding energy and the tamoxifen-pharmacophore fit score of the best ChalcEA derivative (HNS10 were −12.33 kcal/mol and 67.07 kcal/mol, respectively. The HNS10 interacted with Leu346, Thr347, Leu349, Ala350, Glu353, Leu387, Met388, Leu391, Arg394, Met421, and Leu525. These results suggest that the new ChalcEA derivatives could serve as the lead compound for potent ERα inhibitor in the fight against breast cancer.

  17. Molecular Docking and 3D-Pharmacophore Modeling to Study the Interactions of Chalcone Derivatives with Estrogen Receptor Alpha.

    Science.gov (United States)

    Muchtaridi, Muchtaridi; Syahidah, Hasna Nur; Subarnas, Anas; Yusuf, Muhammad; Bryant, Sharon D; Langer, Thierry

    2017-10-16

    Tamoxifen is the most frequently used anti-estrogen adjuvant treatment for estrogen receptor-positive breast cancer. However, it is associated with an increased risk of several serious side-effects, such as uterine cancer, stroke, and pulmonary embolism. The 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) from plant leaves of Eugenia aquea , has been found to inhibit the proliferation of MCF-7 human breast cancer cells in a dose-dependent manner, with an IC 50 of 74.5 μg/mL (250 μM). The aim of this work was to study the molecular interactions of new ChalcEA derivatives formed with the Estrogen Receptor α (ERα) using computer aided drug design approaches. Molecular docking using Autodock 4.2 was employed to explore the modes of binding of ChalcEA derivatives with ERα. The 3D structure-based pharmacophore model was derived using LigandScout 4.1 Advanced to investigate the important chemical interactions of the ERα-tamoxifen complex structure. The binding energy and the tamoxifen-pharmacophore fit score of the best ChalcEA derivative (HNS10) were -12.33 kcal/mol and 67.07 kcal/mol, respectively. The HNS10 interacted with Leu346, Thr347, Leu349, Ala350, Glu353, Leu387, Met388, Leu391, Arg394, Met421, and Leu525. These results suggest that the new ChalcEA derivatives could serve as the lead compound for potent ERα inhibitor in the fight against breast cancer.

  18. Estrogen signaling in the proliferative endometrium: implications in endometriosis

    Directory of Open Access Journals (Sweden)

    Rita de Cássia Pereira da Costa e Silva

    2016-02-01

    Full Text Available SUMMARY Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

  19. Treatment of wastewater having estrogen activity by ionizing radiation

    International Nuclear Information System (INIS)

    Kimura, Atsushi; Taguchi, Mitsumasa; Ohtani, Yoshimi; Shimada, Yoshitaka; Hiratsuka, Hiroshi; Kojima, Takuji

    2007-01-01

    Decomposition of endocrine disrupting chemicals (EDCs) in wastewater was investigated by use of 60 Co γ-ray. Estrogen activities of wastewaters were estimated by the yeast two-hybrid assay based on human or medaka estrogen receptors. The dose required for the elimination of estrogen activity of wastewater below 1 ng dm -3 was about 200 Gy (J kg -1 ). The elimination dose of the estrogen activity depended on the amounts of total organic carbons in wastewater. The economic cost of the treatment process of EDCs using electron beam was estimated at 17 yen m -3

  20. Growth of a progesterone receptor-positive meningioma in a female patient with congenital adrenal hyperplasia.

    Science.gov (United States)

    O'Shea, T; Crowley, R K; Farrell, M; MacNally, S; Govender, P; Feeney, J; Gibney, J; Sherlock, M

    2016-01-01

    Meningioma growth has been previously described in patients receiving oestrogen/progestogen therapy. We describe the clinical, radiological, biochemical and pathologic findings in a 45-year-old woman with congenital adrenal hyperplasia secondary to a defect in the 21-hydroxylase enzyme who had chronic poor adherence to glucocorticoid therapy with consequent virilisation. The patient presented with a frontal headache and marked right-sided proptosis. Laboratory findings demonstrated androgen excess with a testosterone of 18.1 nmol/L (0-1.5 nmol) and 17-Hydroxyprogesterone >180 nmol/L (transsexual patients undergoing therapy with high-dose oestrogen and progestogens. Progesterone receptor positivity has been described previously in meningiomas. 17-Hydroxyprogesterone is elevated in CAH and has affinity and biological activity at the progesterone receptor. Therefore, we hypothesise that patients who have long-standing increased adrenal androgen precursor concentrations may be at risk of meningioma growth. Patients with long-standing CAH (particularly if not optimally controlled) may present with other complications, which may be related to long-standing elevated androgen or decreased glucocorticoid levels.Chronic poor control of CAH is associated with adrenal myelolipoma and adrenal rest tissue tumours.Meningiomas are sensitive to endocrine stimuli including progesterone, oestrogen and androgens as they express the relevant receptors.

  1. Estrogen Modulates Specific Life and Death Signals Induced by LH and hCG in Human Primary Granulosa Cells In Vitro.

    Science.gov (United States)

    Casarini, Livio; Riccetti, Laura; De Pascali, Francesco; Gilioli, Lisa; Marino, Marco; Vecchi, Eugenia; Morini, Daria; Nicoli, Alessia; La Sala, Giovanni Battista; Simoni, Manuela

    2017-04-28

    Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are glycoprotein hormones used for assisted reproduction acting on the same receptor (LHCGR) and mediating different intracellular signaling. We evaluated the pro- and anti-apoptotic effect of 100 pM LH or hCG, in the presence or in the absence of 200 pg/mL 17β-estradiol, in long-term, serum-starved human primary granulosa cells (hGLC) and a transfected granulosa cell line overexpressing LHCGR (hGL5/LHCGR). To this purpose, phospho-extracellular-regulated kinase 1/2 (pERK1/2), protein kinase B (pAKT), cAMP-responsive element binding protein (pCREB) activation and procaspase 3 cleavage were evaluated over three days by Western blotting, along with the expression of target genes by real-time PCR and cell viability by colorimetric assay. We found that LH induced predominant pERK1/2 and pAKT activation STARD1 , CCND2 and anti-apoptotic XIAP gene expression, while hCG mediated more potent CREB phosphorylation, expression of CYP19A1 and procaspase 3 cleavage than LH. Cell treatment by LH is accompanied by increased (serum-starved) cell viability, while hCG decreased the number of viable cells. The hCG-specific, pro-apoptotic effect was blocked by a physiological dose of 17β-estradiol, resulting in pAKT activation, lack of procaspase 3 cleavage and increased cell viability. These results confirm that relatively high levels of steroidogenic pathway activation are linked to pro-apoptotic signals in vitro, which may be counteracted by other factors, i.e., estrogens.

  2. Expression of calbindin-D28k and its regulation by estrogen in the human endometrium during the menstrual cycle

    Directory of Open Access Journals (Sweden)

    Leung Peter CK

    2011-03-01

    Full Text Available Abstract Human endometrium resists embryo implantation except during the 'window of receptivity'. A change in endometrial gene expression is required for the development of receptivity. Uterine calbindin-D28k (CaBP-28k is involved in the regulation of endometrial receptivity by intracellular Ca2+. Currently, this protein is known to be mainly expressed in brain, kidneys, and pancreas, but potential role(s of CaBP-28k in the human uterus during the menstrual cycle remain to be clarified. Thus, in this study we demonstrated the expression of CaBP-28k in the human endometrium in distinct menstrual phases. During the human menstrual cycle, uterine expression levels of CaBP-28k mRNA and protein increased in the proliferative phase and fluctuated in these tissues, compared with that observed in other phases. We assessed the effects of two sex-steroid hormones, 17beta-estradiol (E2 and progesterone (P4, on the expression of CaBP-28k in Ishikawa cells. A significant increase in the expression of CaBP-28k mRNA was observed at the concentrations of E2 (10(-9 to -7 M. In addition, spatial expression of CaBP-28k protein was detected by immunohistochemistry. CaBP-28k was abundantly localized in the cytoplasm of the luminal and glandular epithelial cells during the proliferative phases (early-, mid-, late- and early-secretory phase of menstrual cycle. Taken together, these results indicate that CaBP-28k, a uterine calcium binding protein, is abundantly expressed in the human endometrium, suggesting that uterine expression of CaBP-28k may be involved in reproductive function during the human menstrual cycle.

  3. Estrogens and Androgens in Skeletal Physiology and Pathophysiology

    Science.gov (United States)

    Almeida, Maria; Laurent, Michaël R.; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A.; Bouillon, Roger; Vanderschueren, Dirk

    2016-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. PMID:27807202

  4. Palbociclib in hormone receptor positive advanced breast cancer: A cost-utility analysis.

    Science.gov (United States)

    Raphael, J; Helou, J; Pritchard, K I; Naimark, D M

    2017-11-01

    The addition of palbociclib to letrozole improves progression-free survival in the first-line treatment of hormone receptor positive advanced breast cancer (ABC). This study assesses the cost-utility of palbociclib from the Canadian healthcare payer perspective. A probabilistic discrete event simulation (DES) model was developed and parameterised with data from the PALOMA 1 and 2 trials and other sources. The incremental cost per quality-adjusted life-month (QALM) gained for palbociclib was calculated. A time horizon of 15 years was used in the base case with costs and effectiveness discounted at 5% annually. Time-to- progression and time-to-death were derived from a Weibull and exponential distribution. Expected costs were based on Ontario fees and other sources. Probabilistic sensitivity analyses were conducted to account for parameter uncertainty. Compared to letrozole, the addition of palbociclib provided an additional 14.7 QALM at an incremental cost of $161,508. The resulting incremental cost-effectiveness ratio was $10,999/QALM gained. Assuming a willingness-to-pay (WTP) of $4167/QALM, the probability of palbociclib to be cost-effective was 0%. Cost-effectiveness acceptability curves derived from a probabilistic sensitivity analysis showed that at a WTP of $11,000/QALM gained, the probability of palbociclib to be cost-effective was 50%. The addition of palbociclib to letrozole is unlikely to be cost-effective for the treatment of ABC from a Canadian healthcare perspective with its current price. While ABC patients derive a meaningful clinical benefit from palbociclib, considerations should be given to increase the WTP threshold and reduce the drug pricing, to render this strategy more affordable. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. 25 hydroxy-vitamin D(3)-1alpha hydroxylase expression and activity in cultured human osteoblasts and their modulation by parathyroid hormone, estrogenic compounds and dihydrotestosterone.

    Science.gov (United States)

    Somjen, Dalia; Katzburg, Sara; Stern, Naftali; Kohen, Fortune; Sharon, Orly; Limor, Rona; Jaccard, Niva; Hendel, David; Weisman, Yosef

    2007-01-01

    Human osteoblasts (hOB) produce and respond to 1,25(OH)(2)D(3) (1,25D), suggesting an autocrine/paracrine system. We therefore examined hormonal modulation of the expression and activity of 25 hydroxy-vitamin D(3)-1alpha hydroxylase (1-Ohase) in hOB. Cells from pre- and post-menopausal women or men, were treated with estrogenic compounds and 1-OHase expression and activity were measured. 1-OHase mRNA expression was highest in pre-menopausal women hOB and was increased by all hormones tested. In post-menopausal hOB all hormones except biochainin A (BA) and genistein (G) increased 1-OHase mRNA expressions to less extent. In male-derived hOB only dihydrotestosterone (DHT) and carboxy BA (cBA) increased 1-OHase mRNA expression. 1,25D production from 25(OH)D(3) had a K(m) of approximately 769-400 ng/ml (1.92-1.07 microM) and V(max) of 31.3-17.4 ng/ml (0.078-0.044 microM/60 min/5 x 10(6)cells) respectively, and was increased by all hormones except raloxifene (Ral) with higher stimulation in pre- than in post-menopausal cells. Only BA was almost five times more potent in pre- rather than post-menopausal hOBs. In male hOB only DHT and cBA increased 1,25D production whereas estradiol-17beta (E(2)) had no effect and BA decreased it. These results provide evidence for the expression of 1-OHase mRNA and production of 1,25D in hOBs, which are age and sex dependent and are hormonally modulated. The role of this local autocrine/paracrine 1,25D system in bone physiology deserves further investigation.

  6. Expression of estrogen and progesterone receptors in vestibular schwannomas and their clinical significance

    Directory of Open Access Journals (Sweden)

    Pandey Rakesh

    2009-11-01

    Full Text Available Abstract Objective The objective was to determine the expression of estrogen and progesterone receptors in vestibular schwannomas as well as to determine predictive factors for estrogen and progesterone receptor positivity. Materials and methods The study included 100 cases of vestibular schwannomas operated from January 2006 to June 2009. The clinical details were noted from the medical case files. Formaldehyde-fixed parafiin-embedded archival vestibular schwannomas specimens were used for the immunohistochemical assessment of estrogen and progesterone receptors. Results Neither estrogen nor progesterone receptors could be detected in any of our cases by means of well known immunohistochemical method using well documented monoclonal antibodies. In the control specimens, a strongly positive reaction could be seen. Conclusion No estrogen and progesterone receptor could be found in any of our 100 cases of vestibular schwannomas. Hence our study does not support a causative role of estrogen and progesterone in the growth of vestibular schwannoma as well as hormonal manipulation in the treatment of this tumor.

  7. Perfluorinated chemicals, PFOS and PFOA, enhance the estrogenic effects of 17β-estradiol in T47D human breast cancer cells.

    Science.gov (United States)

    Sonthithai, Pacharapan; Suriyo, Tawit; Thiantanawat, Apinya; Watcharasit, Piyajit; Ruchirawat, Mathuros; Satayavivad, Jutamaad

    2016-06-01

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the two most popular surfactants among perfluorinated compounds (PFCs), with a wide range of uses. Growing evidence suggests that PFCs have the potential to interfere with estrogen homeostasis, posing a risk of endocrine-disrupting effects. This in vitro study aimed to investigate the estrogenic effect of these compounds on T47D hormone-dependent breast cancer cells. PFOS and PFOA (10(-12) to 10(-4)  M) were not able to induce estrogen response element (ERE) activation in the ERE luciferase reporter assay. The ERE activation was induced when the cells were co-incubated with PFOS (10(-10) to 10(-7)  M) or PFOA (10(-9) to 10(-7)  M) and 1 nM of 17β-estradiol (E2). PFOS and PFOA did not modulate the expression of estrogen-responsive genes, including progesterone (PR) and trefoil factor (pS2), but these compounds enhanced the effect of E2-induced pS2 gene expression. Neither PFOS nor PFOA affected T47D cell viability at any of the tested concentrations. In contrast, co-exposure with PFOS or PFOA and E2 resulted in an increase of E2-induced cell viability, but no effect was found with 10 ng ml(-1) EGF co-exposure. Both compounds also intensified E2-dependent growth in the proliferation assay. ERK1/2 phosphorylation was increased by co-exposure with PFOS or PFOA and E2, but not with EGF. Collectively, this study shows that PFOS and PFOA did not possess estrogenic activity, but they enhanced the effects of E2 on estrogen-responsive gene expression, ERK1/2 activation and the growth of the hormone-deprived T47D cells. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  8. Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486 as detected by RNA-sequencing.

    Directory of Open Access Journals (Sweden)

    Karin Tamm-Rosenstein

    Full Text Available BACKGROUND: Estrogen (E2 and progesterone (P4 are key players in the maturation of the human endometrium. The corresponding steroid hormone modulators, tamoxifen (TAM and mifepristone (RU486 are widely used in breast cancer therapy and for contraception purposes, respectively. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiling of the human endometrial Ishikawa cancer cell line treated with E2 and P4 for 3 h and 12 h, and TAM and RU486 for 12 h, was performed using RNA-sequencing. High levels of mRNA were detected for genes, including PSAP, ATP5G2, ATP5H, and GNB2L1 following E2 or P4 treatment. A total of 82 biomarkers for endometrial biology were identified among E2 induced genes, and 93 among P4 responsive genes. Identified biomarkers included: EZH2, MDK, MUC1, SLIT2, and IL6ST, which are genes previously associated with endometrial receptivity. Moreover, 98.8% and 98.6% of E2 and P4 responsive genes in Ishikawa cells, respectively, were also detected in two human mid-secretory endometrial biopsy samples. TAM treatment exhibited both antagonistic and agonistic effects of E2, and also regulated a subset of genes independently. The cell cycle regulator cyclin D1 (CCND1 showed significant up-regulation following treatment with TAM. RU486 did not appear to act as a pure antagonist of P4 and a functional analysis of RU486 response identified genes related to adhesion and apoptosis, including down-regulated genes associated with cell-cell contacts and adhesion as CTNND1, JUP, CDH2, IQGAP1, and COL2A1. CONCLUSIONS: Significant changes in gene expression by the Ishikawa cell line were detected after treatments with E2, P4, TAM, and RU486. These transcriptome data provide valuable insight into potential biomarkers related to endometrial receptivity, and also facilitate an understanding of the molecular changes that take place in the endometrium in the early stages of breast cancer treatment and contraception usage.

  9. [Effects of estrogen on epidermis growth of mice and proliferation of human epidermal cell line HaCaT and its mechanism].

    Science.gov (United States)

    Zhou, Tao; Chen, Jing; Huang, Zongwei; Fang, Li; Chen, Yu; Chen, Yajie; Peng, Yizhi

    2016-05-01

    To observe the effects of estrogen on epidermis growth of mice and proliferation of keratinocytes (human epidermal cell line HaCaT), and to explore its mechanism. (1) Five adult C57BL/6 mice in estrus cycle were identified by vaginal exfoliative cytology diagnosis and set as estrus group, while another 5 adult C57BL/6 mice with ovary resected before sexual development were set as ovariectomized group. The full-thickness skin from the tail root of mice in two groups were collected. The thickness of epidermis was observed and measured after HE staining. The distribution of proliferating cell nuclear antigen (PCNA)-positive cells in epidermis was observed by immunohistochemical staining, the number of which was counted. (2) HaCaT cells in logarithmic growth phase were cultured with RPMI 1640 nutrient solution containing 10% fetal bovine serum, and they were divided into negative control group (NC), pure estradiol group (PE), protein kinase B (Akt) inhibitor group (AI), and extracellular signal-regulated kinase (ERK) inhibitor group (EI) according to the random number table, with 20 wells in each group. To nutrient solution of each group, 1 μL dimethyl sulfoxide, 1 μL 17β-estradiol (100 nmol/L), 1 μL LY294002 (10 μmol/L), and 1 μL PD98059 (30 μmol/L) were added in group NC, group PE, group AI, and group EI respectively, and the last two groups were added with 1 μL 17β-estradiol (100 nmol/L) in addition. At post culture hour (PCH) 0 (immediately after culture), 24, 48, 72, 5 wells of cells from each group were collected to detect the proliferation activity of cells by cell counting kit 8 and microplate reader. (3) HaCaT cells in logarithmic growth phase were collected, grouped, and treated with the above-mentioned methods, with 3 wells in each group. At PCH 72, cell cycle distribution was detected by flow cytometer to calculate proliferation index (PI) of cells. (4) HaCaT cells in logarithmic growth phase were collected, grouped, and treated with the above

  10. Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: A phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy

    Directory of Open Access Journals (Sweden)

    Bastert Gunther

    2008-02-01

    Full Text Available Abstract Background In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS, has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs, including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3–4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established. Methods This study was designed as a multicenter, open-label, single-arm, exploratory phase IIb/III clinical trial of letrozole 2.5 mg, one tablet daily, for 4–8 months. The primary objective was to investigate the effect of neoadjuvant treatment duration on tumor regression and BCS eligibility to identify optimal treatment duration. Tumor regression (by clinical examination, mammography, and ultrasound, shift towards BCS eligibility, and safety assessments were the main outcome measures. Standard parametric and nonparametric descriptive statistics were performed. Results Letrozole treatment was received by 32 of the enrolled 33 postmenopausal women (median (range: 67.0 (56–85 years with unilateral, initially BCS-ineligible primary breast cancer (clinical stage ≥ T2, N0, M0. Letrozole treatment duration in the modified intent-to-treat (ITT; required 4 months' letrozole treatment analysis population (29 patients was 4 months in 14 patients and > 4 months in 15 patients. The respective per-protocol (PP subgroup sizes were 14 and 11. The majority of partial or complete responses were observed at 4 months, though some beneficial responses occurred during prolonged letrozole treatment. Compared with baseline, median tumor size in the ITT population was reduced by 62.5% at Month 4 and by 70.0% at final study visit (Individual End. Similarly, in the PP population, respective reductions were 64.0% and 67.0%. Whereas initially all patients were mastectomy candidates, letrozole treatment enabled BCS (lumpectomy in 22 ITT (75.9% and 18 PP (72.0% patients. Conclusion Over half of patients become BCS-eligible within 4 months of preoperative letrozole treatment. While prolonged treatment for up to 8 months can result in further tumor volume reduction in some patients, there is no clear optimum for treatment duration. Letrozole has a favorable overall safety and tolerability profile. Trial registration ClinicalTrials.gov identifier NCT00535418.

  11. Re-Appraisal of Estrogen Receptor Negative/Progesterone Receptor Positive (ER-/PR+) Breast Cancer Phenotype: True Subtype or Technical Artefact?

    Science.gov (United States)

    Foley, Niamh M; Coll, J M; Lowery, A J; Hynes, S O; Kerin, M J; Sheehan, M; Brodie, C; Sweeney, K J

    2017-09-11

    Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER-/PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management.

  12. Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

    NARCIS (Netherlands)

    Hartog, Hermien; Horlings, Hugo M; van der Vegt, Bert; Kreike, Bas; Ajouaou, Abderrahim; van de Vijver, Marc J; Boezen, Hendrika; de Bock, Geertruida H; van der Graaf, Wilhelmina; Wesseling, Jelle

    2011-01-01

    The insulin-like growth factor type 1 receptor (IGF1R) is involved in progression of breast cancer and resistance to systemic treatment. Targeting IGF1R signaling may, therefore, be beneficial in systemic treatment. We report the effect of IGF1R expression on prognosis in invasive ductal breast

  13. A Role for MEK-Interacting Protein 1 (MP1) in Hormone Responsiveness of Estrogen Receptor-Positive Breast Cancer Cells

    National Research Council Canada - National Science Library

    Conrad, Susan E

    2008-01-01

    The goals of this research are to test the hypothesis that the small scaffold protein MP1 is required for ER function and proliferation of ER- positive breast cancer cells and to characterize the ER/MP1 complex...

  14. Targeting cell necroptosis and apoptosis induced by Shikonin via receptor interacting protein kinases in estrogen receptor positive breast cancer cell line, MCF-7.

    Science.gov (United States)

    Shahsavari, Zahra; Karami-Tehrani, Fatemeh; Salami, Siamak

    2017-09-19

    Recognition of a new therapeutic agent may activate an alternative programmed cell death for the treatment of breast cancer. Here, it has been tried to evaluate the effects of Shikonin, a naphthoquinone derivative of Lithospermum erythrorhizon, on the induction of necroptosis and apoptosis mediated by RIPK1-RIPK3 in the ER+ breast cancer cell line, MCF-7. In the current study, cell death modalities, cell cycle patterns, RIPK1 and RIPK3 expressions, caspase-3 and caspase-8 activities, reactive oxygen species and mitochondrial membrane potential have been evaluated in the Shikonin-treated MCF-7 cells. Necroptosis and apoptosis have been occurred by Shikonin, with a significant increase in RIPK1 and RIPK3 expressions, although necroptosis was the major rout in MCF-7 cells. Shikonin significantly increased the percentage of the cells in sub-G1 and also those in the later stages of cell cycle, which represents an increase in necroptosis and apoptosis. Under caspase inhibition by Z-VAD-FMK, Shikonin has stimulated necroptosis, which could be arrested by Nec-1. An increase in ROS levels and a decrease in the mitochondrial membrane potential have also been observed. On the basis of present findings, Shikonin has been suggested as a good candidate for the induction of cell death in ER+ breast cancer, although further investigations are required. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

    DEFF Research Database (Denmark)

    Alves, Carla Maria Lourenco; Elias, Daniel; Lyng, Maria B

    2016-01-01

    in cell proliferation, apoptosis and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant. RESULTS: We found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6...... expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer.......511, respectively). CONCLUSIONS: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon...

  16. Modeling environmental loading rates of municipal wastewater contaminants: steroidal estrogens

    Science.gov (United States)

    Estrogenic compounds in municipal wastewater are of substantial interest because of suspicion that they may cause reproductive disruption in aquatic invertebrates, and because of their potential to contaminate human drinking water sources. Previous work suggests the primary contr...

  17. Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation.

    NARCIS (Netherlands)

    Moerkens, M.; Zhang, Y.; Wester, L.; Water, van de B.; Meerman, J.H.N.

    2014-01-01

    BACKGROUND Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER) α -positive breast cancer patients. Although the mechanisms behind tamoxifen resistance are still not completely understood, clinical data suggests that increased expression of receptor tyrosine kinases is

  18. Changes in estrogen receptor-alpha and -beta in the infundibular nucleus of the human hypothalamus are related to the occurrence of Alzheimer's disease neuropathology

    NARCIS (Netherlands)

    Hestiantoro, Andon; Swaab, Dick F.

    2004-01-01

    The expression of estrogen receptor (ER)alpha and -beta in the infundibular nucleus of the hypothalamus was studied immunocytochemically in 28 control subjects and 14 patients with Alzheimer's disease (AD). A shift was found from more nuclear staining of ERalpha in young female controls to more

  19. Role of Estrogen and Progesterone in the Survival of Ovarian Tumors — A Study of the Human Ovarian Adenocarcinoma Cell Line OC-117-VGH

    Directory of Open Access Journals (Sweden)

    Kung-Chong Chao

    2005-08-01

    Conclusion: Based on the findings of decreased survival and/or growth in OC-117-VGH ovarian adenocarcinoma cells treated with either estrogen or progesterone, we suspect that both hormones act effectively against ER-negative and PR-negative ovarian cancer cells. These findings should lead to a reassessment of hormone therapy for ovarian cancers.

  20. A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor

    DEFF Research Database (Denmark)

    Chen, Ian Y; Paulmurugan, Ramasamy; Nielsen, Carsten Haagen

    2014-01-01

    firefly luciferase reporter gene (fluc) depends on the binding of its mutant estrogen receptor (ER(G521T)) ligand binding domain (LBD) to an ER ligand such as raloxifene. Mice underwent either intramyocardial or hydrodynamic tail vein (HTV) injection of pcTnT-tTSTA-fluc, followed by differential...

  1. [Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

    Science.gov (United States)

    Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

    2015-06-01

    Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

  2. Xenoestrogens may be the cause of high and increasing rates of hormone receptor positive breast cancer in the world.

    Science.gov (United States)

    Dey, Subhojit; Soliman, Amr S; Merajver, Sofia D

    2009-06-01

    Breast cancer rates are higher in the Western or industrialized world when compared to Africa or Asia. Within the developing world, breast cancer rates are higher in urban areas where people have a more Westernized lifestyle. In addition, there has been a steady increase in the breast cancer incidence across the world. It is already a known fact that the proportion of hormone receptor positive breast cancer cases is higher in the developed world. Evidence from developed countries also shows that most of the increase in breast cancer incidence has been due to an increase in hormone receptor positive breast cancer. Most of the breast cancer incidence can be explained by environmental factors and genetic causes. However, all known risk factors of breast cancer can explain only 30-50% of breast cancer incidence. In the past decade, a number of compounds that affect female hormone homeostasis have been discovered. These xenoestrogens have been shown to cause breast cancer and also induce the expression of hormone receptors in vitro and in vivo. Given the high use of substances containing xenoestrogens in developed regions of the world and their increasing use in urban parts of the developing world, xenoestrogens could be the important cause of high and increasing rates of hormone receptor positive breast cancer across the world. New research in the area of mammary stem cells provides added indication of the probable time period of exposure to xenoestrogens with chronic exposure later in life leading to hormone receptor positive breast cancer and most probable reason behind increasing breast cancer incidence.

  3. Evaluation of a recombinant yeast cell estrogen screening assay.

    OpenAIRE

    Coldham, N G; Dave, M; Sivapathasundaram, S; McDonnell, D P; Connor, C; Sauer, M J

    1997-01-01

    A wide range of chemicals with diverse structures derived from plant and environmental origins are reported to have hormonal activity. The potential for appreciable exposure of humans to such substances prompts the need to develop sensitive screening methods to quantitate and evaluate the risk to the public. Yeast cells transformed with plasmids encoding the human estrogen receptor and an estrogen responsive promoter linked to a reporter gene were evaluated for screening compounds for estroge...

  4. Alterations in three biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor 2) and the Ki67 index between primary and metastatic breast cancer lesions.

    Science.gov (United States)

    Fujii, Kimihito; Watanabe, Rie; Ando, Takahito; Kousaka, Junko; Mouri, Yukako; Yoshida, Miwa; Imai, Tsuneo; Nakano, Shogo; Fukutomi, Takashi

    2017-12-01

    In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast

  5. Optimal systemic therapy for premenopausal women with hormone receptor-positive breast cancer.

    Science.gov (United States)

    Jankowitz, Rachel C; McGuire, Kandace P; Davidson, Nancy E

    2013-08-01

    Although systemic therapy is one of the cornerstones of therapy for premenopausal women with early stage breast cancer, there remain many unknowns regarding its optimal use. By accident of clinical trial design, much clinical investigation in premenopausal women has focused on chemotherapy. More recently the value of endocrine therapy (tamoxifen and ovarian suppression/ablation via surgery, LHRH agonists, or chemotherapy-induced menopause) has become apparent, and some form of endocrine therapy is viewed as standard for virtually all premenopausal women with early stage invasive breast cancer that expresses estrogen and/or progesterone receptor. Critical open questions include type and duration of endocrine therapy and the development of prognostic/predictive markers to help identify patients who are likely to benefit from chemotherapy in addition to endocrine therapy. For some years, five years of tamoxifen has been viewed as the standard endocrine therapy for premenopausal hormone-responsive breast cancer, although the ATLAS trial suggests that an additional five years of tamoxifen can be considered. The MA17 trial also suggests that an additional five years of an aromatase inhibitor can be considered for women who become postmenopausal during tamoxifen therapy. Information about the value of ovarian suppression continues to emerge, most recently with the demonstration of excellent outcome with goserelin plus tamoxifen in the ABCSG12 trial. The SOFT and TEXT trials, whose accrual is now complete, should help to define optimal endocrine therapy. In addition, use of the 21-gene recurrence score assay may help to delineate the additional value of chemotherapy for patients with node-negative breast cancer, and its utility in the setting of women with 1-3 positive lymph nodes is under study in the RxPONDER trial. Nonetheless, the need for other predictive biomarkers to select appropriate therapy remains real. Finally, attention to long term benefits and side effects

  6. Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Keenen MM

    2016-11-01

    Full Text Available Madeline M Keenen,1 Suwon Kim1,2 1Department of Basic Medical Sciences, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, 2Division of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ, USA Abstract: Resistance to antiestrogen therapy remains a significant problem in breast cancer. Low expression of inhibitor of growth 4 (ING4 in primary tumors has been correlated with increased rates of recurrence in estrogen receptor-positive (ER+ breast cancer patients, suggesting a role for ING4 in ER signaling. This study provides evidence that ING4 inhibits ER activity. ING4 overexpression increased the sensitivity of T47D and MCF7 ER+ breast cancer cells to hormone deprivation. ING4 attenuated maximal estrogen-dependent cell growth without affecting the dose–response of estrogen. These results indicated that ING4 functions as a noncompetitive inhibitor of estrogen signaling and may inhibit estrogen-independent ER activity. Supportive of this, treatment with fulvestrant but not tamoxifen rendered T47D cells sensitive to hormone deprivation as did ING4 overexpression. ING4 did not affect nuclear ERα protein expression, but repressed selective ER-target gene transcription. Taken together, these results demonstrated that ING4 inhibited estrogen-independent ER activity, suggesting that ING4-low breast tumors recur faster due to estrogen-independent ER activity that renders tamoxifen less effective. This study puts forth fulvestrant as a proposed therapy choice for patients with ING4-low ER+ breast tumors. Keywords: tamoxifen resistance, transcription repression, PDZK1, TFF1, estrogen independent ERa, fulvestrant  

  7. Estrogen Effects on Wound Healing.

    Science.gov (United States)

    Horng, Huann-Cheng; Chang, Wen-Hsun; Yeh, Chang-Ching; Huang, Ben-Shian; Chang, Chia-Pei; Chen, Yi-Jen; Tsui, Kuan-Hao; Wang, Peng-Hui

    2017-11-03

    Wound healing is a physiological process, involving three successive and overlapping phases-hemostasis/inflammation, proliferation, and remodeling-to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

  8. Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

    Science.gov (United States)

    Gilbert, Emily L.; Ryan, Michael J.

    2015-01-01

    Purpose Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. Methods PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. Findings The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against

  9. Estrogens, Neuroinflammation, and Neurodegeneration

    Science.gov (United States)

    Villa, Alessandro; Vegeto, Elisabetta; Poletti, Angelo

    2016-01-01

    Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a critical review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurological disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases. PMID:27196727

  10. Anaerobic biotransformation of estrogens

    International Nuclear Information System (INIS)

    Czajka, Cynthia P.; Londry, Kathleen L.

    2006-01-01

    Estrogens are important environmental contaminants that disrupt endocrine systems and feminize male fish. We investigated the potential for anaerobic biodegradation of the estrogens 17-α-ethynylestradiol (EE2) and 17-β-estradiol (E2) in order to understand their fate in aquatic and terrestrial environments. Cultures were established using lake water and sediment under methanogenic, sulfate-, iron-, and nitrate-reducing conditions. Anaerobic degradation of EE2 (added at 5 mg/L) was not observed in multiple trials over long incubation periods (over three years). E2 (added at 5 mg/L) was transformed to estrone (E1) under all four anaerobic conditions (99-176 μg L -1 day -1 ), but the extent of conversion was different for each electron acceptor. The oxidation of E2 to E1 was not inhibited by E1. Under some conditions, reversible inter-conversion of E2 and E1 was observed, and the final steady state concentration of E2 depended on the electron-accepting condition but was independent of the total amount of estrogens added. In addition, racemization occurred and E1 was also transformed to 17-α-estradiol under all but nitrate-reducing conditions. Although E2 could be readily transformed to E1 and in many cases 17-α-estradiol under anaerobic conditions, the complete degradation of estrogens under these conditions was minimal, suggesting that they would accumulate in anoxic environments

  11. Anaerobic biotransformation of estrogens

    Energy Technology Data Exchange (ETDEWEB)

    Czajka, Cynthia P. [Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada); Londry, Kathleen L. [Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada)]. E-mail: londryk@cc.umanitoba.ca

    2006-08-31

    Estrogens are important environmental contaminants that disrupt endocrine systems and feminize male fish. We investigated the potential for anaerobic biodegradation of the estrogens 17-{alpha}-ethynylestradiol (EE2) and 17-{beta}-estradiol (E2) in order to understand their fate in aquatic and terrestrial environments. Cultures were established using lake water and sediment under methanogenic, sulfate-, iron-, and nitrate-reducing conditions. Anaerobic degradation of EE2 (added at 5 mg/L) was not observed in multiple trials over long incubation periods (over three years). E2 (added at 5 mg/L) was transformed to estrone (E1) under all four anaerobic conditions (99-176 {mu}g L{sup -1} day{sup -1}), but the extent of conversion was different for each electron acceptor. The oxidation of E2 to E1 was not inhibited by E1. Under some conditions, reversible inter-conversion of E2 and E1 was observed, and the final steady state concentration of E2 depended on the electron-accepting condition but was independent of the total amount of estrogens added. In addition, racemization occurred and E1 was also transformed to 17-{alpha}-estradiol under all but nitrate-reducing conditions. Although E2 could be readily transformed to E1 and in many cases 17-{alpha}-estradiol under anaerobic conditions, the complete degradation of estrogens under these conditions was minimal, suggesting that they would accumulate in anoxic environments.

  12. Yeast Estrogen Screen Assay as a Tool for Detecting Estrogenic Activity in Water Bodies

    Directory of Open Access Journals (Sweden)

    Mirjana Bistan

    2012-01-01

    Full Text Available The presence of endocrine-disrupting compounds in wastewater, surface water, groundwater and even drinking water has become a major concern worldwide, since they negatively affect wildlife and humans. Therefore, these substances should be effectively removed from effluents before they are discharged into surface water to prevent pollution of groundwater, which can be a source of drinking water. Furthermore, an efficient control of endocrine-disrupting compounds in wastewater based on biological and analytical techniques is required. In this study, a yeast estrogen screen (YES bioassay has been introduced and optimized with the aim to assess potential estrogenic activity of waters. First, assay duration, concentration of added substrate to the assay medium and wavelength used to measure the absorbance of the substrate were estimated. Several compounds, such as 17-β-estradiol, 17-α-ethinylestradiol, bisphenol A, nonylphenol, genisteine, hydrocortisone, dieldrin, atrazine, methoxychlor, testosterone and progesterone were used to verify its specificity and sensitivity. The optimized YES assay was sensitive and responded specifically to the selected estrogenic and nonestrogenic compounds in aqueous samples. Potential estrogenicity of influent and effluent samples of two wastewater treatment plants was assessed after the samples had been concentrated by solid-phase extraction (SPE procedure using Oasis® HLB cartridges and methanol as eluting solvent. Up to 90 % of relative estrogenic activity was detected in concentrated samples of influents to wastewater treatment plants and estrogenic activity was still present in the concentrated effluent samples. We found that the introduced YES assay is a suitable screening tool for monitoring the potential estrogenicity of effluents that are discharged into surface water.

  13. Activation of p53, inhibition of telomerase activity and induction of estrogen receptor beta are associated with the anti-growth effects of combination of ovarian hormones and retinoids in immortalized human mammary epithelial cells

    Directory of Open Access Journals (Sweden)

    Smith-Schneider Sallie

    2005-03-01

    Full Text Available Abstract Background A full-term pregnancy has been associated with reduced risk for developing breast cancer. In rodent models, the protective effect of pregnancy can be mimicked with a defined regimen of estrogen and progesterone combination (E/P. However, the effects of pregnancy levels of E/P in humans and their underlying mechanisms are not fully understood. In this report, we investigated the growth inhibitory effects of pregnancy levels of E/P and both natural and synthetic retinoids in an immortalized human mammary epithelial cell line, 76N TERT cell line. Results We observed that cell growth was modestly inhibited by E/P, 9-cis-retinoic acid (9-cis RA or all-trans-retinoic acid (ATRA, and strongly inhibited by N-(4-hydroxyphenyl retinamide (HPR. The growth inhibitory effects of retinoids were further increased in the presence of E/P, suggesting their effects are additive. In addition, our results showed that both E/P and retinoid treatments resulted in increased RARE and p53 gene activity. We further demonstrated that p53 and p21 protein expression were induced following the E/P and retinoid treatments. Furthermore, we demonstrated that while the telomerase activity was moderately inhibited by E/P, 9-cis RA and ATRA, it was almost completely abolished by HPR treatment. These inhibitions on telomerase activity by retinoids were potentiated by co-treatment with E/P, and correlated well with their observed growth inhibitory effects. Finally, this study provides the first evidence that estrogen receptor beta is up-regulated in response to E/P and retinoid treatments. Conclusion Taken together, our studies show that part of the anti-growth effects of E/P and retinoids is p53 dependent, and involve activation of p53 and subsequent induction of p21 expression. Inhibition of telomerase activity and up-regulation of estrogen receptor beta are also associated with the E/P- and retinoid-mediated growth inhibition. Our studies also demonstrate that

  14. Effects of phytoestrogens and environmental estrogens on osteoblastic differentiation in MC3T3-E1 cells

    International Nuclear Information System (INIS)

    Kanno, Sanae; Hirano, Seishiro; Kayama, Fujio

    2004-01-01

    Phytoestrogens and environmental estrogens, which have in part some structural similarity to 17β-estradiol, are reported to act as agonists/antagonists of estrogen in animals and humans. Estrogen is known to play an important role in maintaining bone mass, since the concentration of serum estrogen decreases after menopause and the estrogen deficiency results in bone loss. In this study, we report the effects of phytoestrogens (genistein, daidzein, and coumestrol) and environmental estrogens (bisphenol A (BPA), p-n-nonylphenol (NP) and bis(2-ethylhexyl)phthalate (DEHP)) on osteoblast differentiation using MC3T3-E1 cells, a mouse calvaria osteoblast-like cell line. Coumestrol (10 -10 to 10 -6 M) slightly enhanced cell proliferation, while neither the other phytoestrogens (daidzein, genistein) nor environmental estrogens increased cell proliferation. Alkaline phosphatase (ALP) activity and cellular calcium (Ca) and phosphorus (P) contents were increased by phytoestrogens and BPA; however, neither NP nor DEHP affected those osteoblastic indicators. The effects of estrogenic potency, using the cell proliferation of MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line, indicate that coumestrol has the highest estrogenic potency among those phytoestrogens and environmental estrogens. The estrogenic potency of NP and DEHP were lower than the others. In conclusion, phytoestrogens, such as coumestrol, genistein and daidzein, and BPA increased ALP activity and enhanced bone mineralization in MC3T3-E1 cells, suggesting that not only phytoestrogen but also BPA, an environmental estrogen, is implicated in bone metabolism

  15. KBERG: KnowledgeBase for Estrogen Responsive Genes

    DEFF Research Database (Denmark)

    Tang, Suisheng; Zhang, Zhuo; Tan, Sin Lam

    2007-01-01

    Estrogen has a profound impact on human physiology affecting transcription of numerous genes. To decipher functional characteristics of estrogen responsive genes, we developed KnowledgeBase for Estrogen Responsive Genes (KBERG). Genes in KBERG were derived from Estrogen Responsive Gene Database...... (ERGDB) and were analyzed from multiple aspects. We explored the possible transcription regulation mechanism by capturing highly conserved promoter motifs across orthologous genes, using promoter regions that cover the range of [-1200, +500] relative to the transcription start sites. The motif detection...... is based on ab initio discovery of common cis-elements from the orthologous gene cluster from human, mouse and rat, thus reflecting a degree of promoter sequence preservation during evolution. The identified motifs are linked to transcription factor binding sites based on the TRANSFAC database. In addition...

  16. Estrogens and male reproduction: a new concept

    Directory of Open Access Journals (Sweden)

    S. Carreau

    2007-06-01

    Full Text Available The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19 in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ß in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

  17. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer.

    Science.gov (United States)

    Mishra, Sweta; Tai, Qin; Gu, Xiang; Schmitz, James; Poullard, Ashley; Fajardo, Roberto J; Mahalingam, Devalingam; Chen, Xiaodong; Zhu, Xueqiong; Sun, Lu-Zhe

    2015-12-29

    The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.

  18. Predictive value of Ki67 for adjuvant chemotherapy in node-negative, hormone receptor-positive breast cancer.

    Science.gov (United States)

    Sutepvarnon, Apisada; Warnnissorn, Malee; Srimuninnimit, Vichien

    2013-02-01

    Ki67 labeling index (Ki67 LI) is a measure of tumor proliferation. In breast cancer, evidence supporting its prognostic value is clear and its predictive value for response to treatment finds some benefits. However studies of Ki67 LI as a predictive marker in early breast cancer are still limited worldwide and there is no data in Thailand. To assess the predictive value of Ki67 expression for adjuvant chemotherapy in patients with node-negative, hormone receptor-positive breast cancer The authors retrospectively evaluated 127 diagnosed early breast cancer with node-negative, hormone receptor-positive patients and receiving adjuvant systemic treatment at Siriraj hospital. Disease free survival (DFS) was compared with the log-rank test according to Ki67 LI and adjuvant systemic treatment (chemoendocrine therapy and endocrine therapy alone). At a median follow-up of 3.3 years. The 5-year DFS rate was 79% for patients with low Ki67 expression and 75% for patients with high Ki67 expression. Of the 127 patients, 56 (44.1%) received chemoendocrine therapy and 71 (55.9%) were treated with endocrine therapy alone. There was no different effect of DFS among those receiving adjuvant endocrine therapy alone and those receiving adjuvant chemoendocrine therapy depending on Ki67 expression. Among patients with node-negative, hormone receptor-positive breast cancer, a high Ki67 LI had worse DFS trend than a low Ki67 LI but the Ki67 LI did not predict the efficacy of adjuvant chemotherapy.

  19. Comparison of in vitro estrogenic activity and estrogen concentrations in source and treated waters from 25 U.S. drinking water treatment plants.

    Science.gov (United States)

    Conley, Justin M; Evans, Nicola; Mash, Heath; Rosenblum, Laura; Schenck, Kathleen; Glassmeyer, Susan; Furlong, Ed T; Kolpin, Dana W; Wilson, Vickie S

    2017-02-01

    In vitro bioassays have been successfully used to screen for estrogenic activity in wastewater and surface water, however, few have been applied to treated drinking water. Here, extracts of source and treated water samples were assayed for estrogenic activity using T47D-KBluc cells and analyzed by liquid chromatography-Fourier transform mass spectrometry (LC-FTMS) for natural and synthetic estrogens (including estrone, 17β-estradiol, estriol, and ethinyl estradiol). None of the estrogens were detected above the LC-FTMS quantification limits in treated samples and only 5 source waters had quantifiable concentrations of estrone, whereas 3 treated samples and 16 source samples displayed in vitro estrogenicity. Estrone accounted for the majority of estrogenic activity in respective samples, however the remaining samples that displayed estrogenic activity had no quantitative detections of known estrogenic compounds by chemical analyses. Source water estrogenicity (max, 0.47ng 17β-estradiol equivalents (E2Eq) L -1 ) was below levels that have been linked to adverse effects in fish and other aquatic organisms. Treated water estrogenicity (max, 0.078ngE2EqL -1 ) was considerably below levels that are expected to be biologically relevant to human consumers. Overall, the advantage of using in vitro techniques in addition to analytical chemical determinations was displayed by the sensitivity of the T47D-KBluc bioassay, coupled with the ability to measure cumulative effects of mixtures, specifically when unknown chemicals may be present. Published by Elsevier B.V.

  20. Estrogenic compounds -endocrine disruptors

    OpenAIRE

    Munteanu Constantin; Hoteteu Mihai

    2011-01-01

    Endocrine disruptors (polychlorinated biphenyls, dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides) are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inf...

  1. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds

    International Nuclear Information System (INIS)

    Lee, Soo Yeun; Oh, Seung Min; Chung, Kyu Hyuck

    2006-01-01

    Chronic exposure to marijuana produces adverse effects on the endocrine and reproductive systems in humans; however, the experimental evidence for this presented thus far has not been without controversy. In this study, the estrogenic effect of marijuana smoke condensate (MSC) was evaluated using in vitro bioassays, viz., the cell proliferation assay, the reporter gene assay, and the ER competitive binding assay. The results of these assays were compared with those of three major cannabinoids, i.e., THC, CBD, and CBN. The estrogenic effect of MSC was further confirmed by the immature female rat uterotrophic assay. MSC stimulated the estrogenicity related to the ER-mediated pathway, while neither THC, CBD, nor CBN did. Moreover, treatment with 10 and 25 mg/kg MSC induced significant uterine response, and 10 mg/kg MSC resulted in an obvious change in the uterine epithelial cell appearance. MSC also enhanced the IGFBP-1 gene expression in a dose-dependent manner. To identify the constituents of MSC responsible for its estrogenicity, the MSC fractionated samples were examined using another cell proliferation assay, and the estrogenic active fraction was analyzed using GC-MS. In the organic acid fraction that showed the strongest estrogenic activity among the seven fractions of MSC, phenols were identified. Our results suggest that marijuana abuse is considered an endocrine-disrupting factor. Furthermore, these results suggest that the phenolic compounds contained in MSC play a role in its estrogenic effect

  2. Computational estimation of rainbow trout estrogen receptor binding affinities for environmental estrogens

    International Nuclear Information System (INIS)

    Shyu, Conrad; Cavileer, Timothy D.; Nagler, James J.; Ytreberg, F. Marty

    2011-01-01

    Environmental estrogens have been the subject of intense research due to their documented detrimental effects on the health of fish and wildlife and their potential to negatively impact humans. A complete understanding of how these compounds affect health is complicated because environmental estrogens are a structurally heterogeneous group of compounds. In this work, computational molecular dynamics simulations were utilized to predict the binding affinity of different compounds using rainbow trout (Oncorhynchus mykiss) estrogen receptors (ERs) as a model. Specifically, this study presents a comparison of the binding affinity of the natural ligand estradiol-17β to the four rainbow trout ER isoforms with that of three known environmental estrogens 17α-ethinylestradiol, bisphenol A, and raloxifene. Two additional compounds, atrazine and testosterone, that are known to be very weak or non-binders to ERs were tested. The binding affinity of these compounds to the human ERα subtype is also included for comparison. The results of this study suggest that, when compared to estradiol-17β, bisphenol A binds less strongly to all four receptors, 17α-ethinylestradiol binds more strongly, and raloxifene has a high affinity for the α subtype only. The results also show that atrazine and testosterone are weak or non-binders to the ERs. All of the results are in excellent qualitative agreement with the known in vivo estrogenicity of these compounds in the rainbow trout and other fishes. Computational estimation of binding affinities could be a valuable tool for predicting the impact of environmental estrogens in fish and other animals.

  3. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    International Nuclear Information System (INIS)

    Annab, Lois A; Hawkins, Rebecca E; Solomon, Greg; Barrett, J Carl; Afshari, Cynthia A

    2000-01-01

    phosphoprotein that is regulated in response to DNA damaging agents [5,6,7] and in response to estrogen-induced growth [8,9,10,11]. Germline mutations that cause breast and ovarian cancer predisposition frequently result in truncated and presumably inactive BRCA1 protein [12]. BG-1 cells were derived from a patient with stage III, poorly differentiated ovarian adenocarcinoma [13]. This cell line, which expresses wild-type BRCA1, is estrogen responsive and withdrawal of estrogen results in eventual cell death. Previous studies suggest that BRCA1 is stimulated as a result of estrogen treatment [8,9,10,11], and also that BRCA1 may be involved in the cell death process [14]. Therefore, we examined the effect of reduction of BRCA1 levels in BG-1 cells on the cellular response to hormone depletion as well as estrogen stimulation. The results suggest that reduced levels of BRCA1 correlates with a survival advantage when BG-1 cells are placed under growth-restrictive and hormone-depleted conditions. In optimum growth conditions, significantly reduced levels of BRCA1 correlates with enhanced growth both in vitro and in vivo. To test the hypothesis that BRCA1 may play a role in the regulation of ovarian tumor cell death as well as in the inhibition of ovarian cell proliferation. The estrogen receptor-positive, BG-1 cell line [13], which contains an abundant amount of estrogen receptors (600 fmoles/100 μg DNA), was infected using a pLXSN retroviral vector (provided by AD Miller) containing an inverted partial human cDNA 900-base-pair sequence of BRCA1 (from nucleotide 121 in exon 1 to nucleotide 1025 in exon 11, accession #U14680). After 2 weeks of selection in 800 μg/ml of geneticin-G418 (Gibco/Life Technologies, Gaithersburg, MD, USA), BG-1 G418-resistant colonies were pooled, or individually isolated, and assayed for growth in the presence or absence of supplemented estrogen. Virally infected pooled populations of BG-1 cells were examined for BRCA1 message levels by ribonuclease

  4. Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Pinto, Caroline [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056 (United States); Grimaldi, Marina; Boulahtouf, Abdelhay [Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé de la Recherche Médicale U896, Institut Régional de Cancérologie de Montpellier, Université Montpellier 1, 34298 Montpellier (France); Pakdel, Farzad [Institut de Recherche sur la Santé, Environnement et Travail (IRSET), INSERM U1085, Université de Rennes 1, Rennes (France); Brion, François; Aït-Aïssa, Sélim [Unité Écotoxicologie In Vitro et In Vivo, INERIS, Parc ALATA, 60550 Verneuil-en-Halatte (France); Cavaillès, Vincent [Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé de la Recherche Médicale U896, Institut Régional de Cancérologie de Montpellier, Université Montpellier 1, 34298 Montpellier (France); Bourguet, William [U1054, Centre de Biochimie Structurale, CNRS UMR5048, Université Montpellier 1 et 2, 34290 Montpellier (France); Gustafsson, Jan-Ake [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056 (United States); Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge (Sweden); and others

    2014-10-01

    Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28 °C as compared to 37 °C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. - Highlights: • Zebrafish is increasingly used to study the effects of estrogens. • We assessed the activity of pharmaceutical and environmental estrogens on zfERs. • Environmental estrogens displayed greater potency for zfERα compared to zfERβs. • hERβ selective agonists displayed greater potency for zf

  5. Defining the cellular precursors to human breast cancer

    Science.gov (United States)

    Keller, Patricia J.; Arendt, Lisa M.; Skibinski, Adam; Logvinenko, Tanya; Klebba, Ina; Dong, Shumin; Smith, Avi E.; Prat, Aleix; Perou, Charles M.; Gilmore, Hannah; Schnitt, Stuart; Naber, Stephen P.; Garlick, Jonathan A.; Kuperwasser, Charlotte

    2012-01-01

    Human breast cancers are broadly classified based on their gene-expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast: luminal (EpCAM+) and basal/myoepithelial (CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer, including estrogen receptor-positive and estrogen receptor-negative tumors with luminal and basal-like characteristics, respectively, whereas transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is attributable, in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues. PMID:21940501

  6. The histone demethylase LSD1 is required for estrogen-dependent S100A7 gene expression in human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Seung Eun [Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Yonsei Biomolecule Research Initiative, Yonsei University, Seoul 120-749 (Korea, Republic of); Jang, Yeun Kyu, E-mail: ykjang@yonsei.ac.kr [Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Yonsei Biomolecule Research Initiative, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer S100A7 gene is up-regulated in response to estrogen in breast cancer cells. Black-Right-Pointing-Pointer Histone demethylase LSD1 can associate physically with S100A7 gene promoters. Black-Right-Pointing-Pointer E2-induced S100A7 expression requires the enzymatic activity of LSD1. Black-Right-Pointing-Pointer S100A7 inhibits cell proliferation, implying its tumor suppressor-like function. -- Abstract: S100A7, a member of S100 calcium binding protein family, is highly associated with breast cancer. However, the molecular mechanism of S100A7 regulation remains unclear. Here we show that long-term treatment with estradiol stimulated S100A7 expression in MCF7 breast cancer cells at both the transcriptional and translational levels. Both treatment with a histone demethylase LSD1 inhibitor and shRNA-based knockdown of LSD1 expression significantly decreased 17{beta}-estradiol (E2)-induced S100A7 expression. These reduced E2-mediated S100A7 expression are rescued by the overexpressed wild-type LSD1 but not by its catalytically inactive mutant. Our data showed in vivo association of LSD1 with S100A7 promoters, confirming the potential role of LSD1 in regulating S100A7 expression. S100A7 knockdown increased both normal cell growth and estrogen-induced cell proliferation, suggesting a negative influence by S100A7 on the growth of cancer cells. Together, our data suggest that estrogen-induced S100A7 expression mediated by the histone demethylase LSD1 may downregulate breast cancer cell proliferation, implying a potential tumor suppressor-like function for S100A7.

  7. The histone demethylase LSD1 is required for estrogen-dependent S100A7 gene expression in human breast cancer cells

    International Nuclear Information System (INIS)

    Yu, Seung Eun; Jang, Yeun Kyu

    2012-01-01

    Highlights: ► S100A7 gene is up-regulated in response to estrogen in breast cancer cells. ► Histone demethylase LSD1 can associate physically with S100A7 gene promoters. ► E2-induced S100A7 expression requires the enzymatic activity of LSD1. ► S100A7 inhibits cell proliferation, implying its tumor suppressor-like function. -- Abstract: S100A7, a member of S100 calcium binding protein family, is highly associated with breast cancer. However, the molecular mechanism of S100A7 regulation remains unclear. Here we show that long-term treatment with estradiol stimulated S100A7 expression in MCF7 breast cancer cells at both the transcriptional and translational levels. Both treatment with a histone demethylase LSD1 inhibitor and shRNA-based knockdown of LSD1 expression significantly decreased 17β-estradiol (E2)-induced S100A7 expression. These reduced E2-mediated S100A7 expression are rescued by the overexpressed wild-type LSD1 but not by its catalytically inactive mutant. Our data showed in vivo association of LSD1 with S100A7 promoters, confirming the potential role of LSD1 in regulating S100A7 expression. S100A7 knockdown increased both normal cell growth and estrogen-induced cell proliferation, suggesting a negative influence by S100A7 on the growth of cancer cells. Together, our data suggest that estrogen-induced S100A7 expression mediated by the histone demethylase LSD1 may downregulate breast cancer cell proliferation, implying a potential tumor suppressor-like function for S100A7.

  8. Channel catfish (Ictalurus punctatus) leukocytes express estrogen receptor isoforms ERα and ERβ2 and are functionally modulated by estrogens

    Science.gov (United States)

    Iwanowicz, Luke R.; Stafford, James L.; Patiño, Reynaldo; Bengten, Eva; Miller, Norman W.; Blazer, Vicki

    2014-01-01

    Estrogens are recognized as modulators of immune responses in mammals and teleosts. While it is known that the effects of estrogens are mediated via leukocyte-specific estrogen receptors (ERs) in humans and mice, leucocyte-specific estrogen receptor expression and the effects of estrogens on this cell population is less explored and poorly understood in teleosts. Here in, we verify that channel catfish (Ictalurus punctaus) leukocytes express ERα and ERβ2. Transcripts of these isoforms were detected in tissue-associated leukocyte populations by PCR, but ERβ2 was rarely detected in PBLs. Expression of these receptors was temporally regulated in PBLs following polyclonal activation by concanavalin A, lipopolysaccharide or alloantigen based on evaluation by quantitative and end-point PCR. Examination of long-term leukocyte cell lines demonstrated that these receptors are differentially expressed depending on leukocyte lineage and phenotype. Expression of ERs was also temporally dynamic in some leukocyte lineages and may reflect stage of cell maturity. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. Similarly, bactericidal activity and phorbol 12-myristate 13-acetate induced respiratory burst was modulated by 17β-estradiol. These actions were blocked by the pure ER antagonist ICI 182780 indicating that response is, in part, mediated via ERα. In summary, estrogen receptors are expressed in channel catfish leukocytes and participate in the regulation of the immune response. This is the first time leukocyte lineage expression has been reported in teleost cell lines.

  9. Confirmation of 5p12 as a susceptibility locus for progesterone-receptor- positive, lower grade breast cancer

    NARCIS (Netherlands)

    R.L. Milne (Roger); E.L. Goode (Ellen); M. García-Closas (Montserrat); F.J. Couch (Fergus); G. Severi (Gianluca); R. Hein (Rebecca); Z. Fredericksen (Zachary); N. Malats (Núria); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); J. Benítez (Javier); T. Dörk (Thilo); P. Schürmann (Peter); J.H. Karstens (Johann); P. Hillemanns (Peter); A. Cox (Angela); I.W. Brock (Ian); K.S. Elliot (Katherine); S.S. Cross (Simon); S. Seal (Sheila); C. Turnbull (Clare); A. Renwick (Anthony); N. Rahman (Nazneen); C-Y. Shen (Chen-Yang); J-C. Yu (Jyh-Cherng); C.-S. Huang (Chiun-Sheng); M.-F. Hou (Ming-Feng); B.G. Nordestgaard (Børge); S.E. Bojesen (Stig); C. Lanng (Charlotte); G.G. Alnæs (Grethe); V. Kristensen (Vessela); A.-L. Børrensen-Dale (Anne-Lise); J.L. Hopper (John); G.S. Dite (Gillian); C. Apicella (Carmel); M.C. Southey (Melissa); D. Lambrechts (Diether); B.T. Yesilyurt (Betül); O.A.M. Floris; K. Leunen; S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); G.G. Giles (Graham); L. Baglietto (Laura); E.M. John (Esther); A. Miron (Alexander); S.J. Chanock (Stephen); J. Lissowska (Jolanta); M.E. Sherman (Mark); J.D. Figueroa (Jonine); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); I.V. Zalutsky (Iosif); Y.I. Rogov (Yuri); P.A. Fasching (Peter); T. Bayer (T.); A.B. Ekici (Arif); M.W. Beckmann (Matthias); H. Brenner (Hermann); H. Müller (Heike); V. Arndt (Volker); C. Stegmaier (Christa); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A.M. Mulligan (Anna Marie); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); A. Meindl (Alfons); J. Heil (Joerg); C.R. Bartram (Claus); R.K. Schmutzler (Rita); G. Thomas (Gilles); R.N. Hoover (Robert); O. Fletcher (Olivia); L.J. Gibson (Lorna); I. dos Santos Silva (Isabel); J. Peto (Julian); S. Nickels (Stefan); D. Flesch-Janys (Dieter); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.J. van 't Veer (Laura); R.A.E.M. Tollenaar (Rob); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); K.A. Pooley (Karen); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); B. Burwinkel (Barbara); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); D. Kang (Daehee); K-Y. Yoo (Keun-Young); D-Y. Noh (Dong-Young); S.-H. Ahn (Sei-Hyun); D. Hunter (David); S.E. Hankinson (Susan); P. Kraft (Peter); S. Lindstrom (Stephen); X. Chen (Xiaoqing); J. Beesley (Jonathan); U. Hamann (Ute); V. Harth (Volker); C. Justenhoven (Christina); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); R.A. Oldenburg (Rogier); M.M.A. Tilanus-Linthorst (Madeleine); E.K. Khusnutdinova (Elza); M. Bermisheva (Marina); D. Prokofieva (Darya); A. Farahtdinova (Albina); J.E. Olson (Janet); X. Wang (Xing); M.K. Humphreys (Manjeet); Q. Wang (Qing); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas)

    2011-01-01

    textabstractBackground: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer

  10. Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer

    NARCIS (Netherlands)

    Milne, Roger L.; Goode, Ellen L.; Garca-Closas, Montserrat; Couch, Fergus J.; Severi, Gianluca; Hein, Rebecca; Fredericksen, Zachary; Malats, Nuria; Pilar Zamora, M.; Arias Perez, Jose Ignacio; Benitez, Javier; Doerk, Thilo; Schuermann, Peter; Karstens, Johann H.; Hillemanns, Peter; Cox, Angela; Brock, Ian W.; Elliot, Graeme; Cross, Simon S.; Seal, Sheila; Turnbull, Clare; Renwick, Anthony; Rahman, Nazneen; Shen, Chen-Yang; Yu, Jyh-Cherng; Huang, Chiun-Sheng; Hou, Ming-Feng; Nordestgaard, Borge G.; Bojesen, Stig E.; Lanng, Charlotte; Alnaes, Grethe Grenaker; Kristensen, Vessela; Borrensen-Dale, Anne-Lise; Hopper, John L.; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Lambrechts, Diether; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Chang-Claude, Jenny; Wang-Gohrke, Shan; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Giles, Graham G.; Baglietto, Laura; John, Esther M.; Miron, Alexander; Chanock, Stephen J.; Lissowska, Jolanta; Sherman, Mark E.; Figueroa, Jonine D.; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Zalutsky, Iosif V.; Rogov, Yuri I.; Fasching, Peter A.; Bayer, Christian M.; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Mueller, Heiko; Arndt, Volker; Stegmaier, Christa; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Meindl, Alfons; Heil, Joerg; Bartram, Claus R.; Schmutzler, Rita K.; Thomas, Gilles D.; Hoover, Robert N.; Fletcher, Olivia; Gibson, Lorna J.; Silva, Isabel dos Santos; Peto, Julian; Nickels, Stefan; Flesch-Janys, Dieter; Anton-Culver, Hoda; Ziogas, Argyrios; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Tollenaar, Rob A. E. M.; Pharoah, Paul D. P.; Dunning, Alison M.; Pooley, Karen A.; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Kraft, Peter; Lindstrom, Sara; Chen, Xiaoqing; Beesley, Jonathan; Hamann, Ute; Harth, Volker; Justenhoven, Christina; Winqvist, Robert; Pylkas, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Hooning, Maartje; Hollestelle, Antoinette; Oldenburg, Rogier A.; Tilanus-Linthorst, Madeleine; Khusnutdinova, Elza; Bermisheva, Marina; Prokofieva, Darya; Farahtdinova, Albina; Olson, Janet E.; Wang, Xianshu; Humphreys, Manjeet K.; Wang, Qin; Chenevix-Trench, Georgia; Easton, Douglas F.

    2011-01-01

    Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association

  11. Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer

    DEFF Research Database (Denmark)

    Milne, Roger L; Goode, Ellen L; García-Closas, Montserrat

    2011-01-01

    BACKGROUND: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Associatio...

  12. Deuterium-labeled steroids for study in humans. II. Preliminary studies on estrogen production rates in pre- and post-menopausal women

    Energy Technology Data Exchange (ETDEWEB)

    Pinkus, J.L.; Charles, D.; Chattoraj, S.C.

    1979-01-01

    6,7-Dideuterio-3-hydroxy-1,3,5(10)-estratrien-17-one (dideuterio-estrone) and 4-deuterio-1,3,5(10)-estratriene-3,17 beta-diol (monodeuterio-17 beta-estradiol) were used for the estimation of estrogen production rates in pre- and post-menopausal women. The results are concordant with those obtained by radioisotope administration as reported in the literature. This preliminary study suggests that one or more steroids labeled with one or multiple deuterium and/or other stable isotopes may be employed for the measurement of production rates of steroid hormones which are derived from multiple precursors.

  13. The reliability of rabbit monoclonal antibodies in the immunohistochemical assessment of estrogen receptors, progesterone receptors, and HER2 in human breast carcinomas

    OpenAIRE

    Rhodes, A.; Sarson, J.; Assam, E. E.; Dean, S. J.; Cribb, E. C.; Parker, A.

    2010-01-01

    The reliability of the rabbit monoclonal antibodies SP1, SP2, SP3, and 4B5 was immunohistochemically assessed on a range of 96 invasive breast and carcinomas and the results compared with those achieved with established antibody markers for estrogen receptors (6F11), progesterone receptors (PgR636), and HER2 (polyclonal A0485 and clone CB11), with HER2 status validated by fluorescence in situ hybridization (FISH) and silver in situ hybridization. Optimal results depended on the duration of mi...

  14. Estrogen effects on the breast

    International Nuclear Information System (INIS)

    Berkowitz, J.E.; Goldblum, L.E.; Gatewood, O.M.B.; Gayler, B.W.

    1988-01-01

    Estrogen is frequently used in postmenopausal women for the treatment of menopausal symptoms and for prevention of osteoporosis. Little mention of estrogen effects on the postmenopausal breast is found in the literature. It has been suggested that estrogen replacement therapy may cause proliferative changes in the breast, manifested by mammographically dense breasts. The authors present five patients in whom the fibroglandular tissue dramatically increased after initiation of hormonal therapy. One patient's mammogram returned to baseline 2 weeks after discontinuation of treatment. Recognition of the estrogen effect is important since appearing densities are cause for suspicion in the postmenopausal breast and since very dense breasts can obscure masses

  15. Estrogens regulate the hepatic effects of Growth Hormone, a hormonal interplay with multiple fates

    Directory of Open Access Journals (Sweden)

    Leandro eFernandez-Perez

    2013-06-01

    Full Text Available The liver responds to estrogens and GH which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk with endocrine, metabolic, and sex-differentiated functions of GH. Most previous studies have been focused on the influence of estrogens on pituitary GH secretion, which has a great impact on hepatic transcriptional regulation. However, there is strong evidence that estrogens can influence the GH-regulated endocrine and metabolic functions in the human liver by acting at the level of GHR-STAT5 signaling pathway. This cross-talk is relevant because the widespread exposition of estrogen or estrogen-related compounds in human. Therefore, GH or estrogen signaling deficiency as well as the influence of estrogens on GH biology can cause a dramatic impact in liver physiology during mammalian development and in adulthood. In this review, we will summarize the current status of the influence of estrogen on GH actions in liver. A better understanding of estrogen-GH interplay in liver will lead to improved therapy of children with growth disorders and of adults with GH deficiency.

  16. An Assessment of Potential Exposure and Risk from Estrogens in Drinking Water

    OpenAIRE

    Caldwell, Daniel J.; Mastrocco, Frank; Nowak, Edward; Johnston, James; Yekel, Harry; Pfeiffer, Danielle; Hoyt, Marilyn; DuPlessie, Beth M.; Anderson, Paul D.

    2009-01-01

    Background Detection of estrogens in the environment has raised concerns in recent years because of their potential to affect both wildlife and humans. Objectives We compared exposures to prescribed and naturally occurring estrogens in drinking water to exposures to naturally occurring background levels of estrogens in the diet of children and adults and to four independently derived acceptable daily intakes (ADIs) to determine whether drinking water intakes are larger or smaller than dietary...

  17. Estrogenic compounds -endocrine disruptors

    Directory of Open Access Journals (Sweden)

    Munteanu Constantin

    2011-11-01

    Full Text Available Endocrine disruptors (polychlorinated biphenyls, dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inflammation, Sertoli-cell-only pattern, hypospadias, altered pituitary and thyroid gland functions are also observed, the available data are insufficient to deduce worldwide conclusions.

  18. ESTROGEN IN THE LIMBIC SYSTEM

    NARCIS (Netherlands)

    ter Horst, Gert J.; Litwack, G

    2010-01-01

    Estrogens are a group of steroid hormones that function as the primary female sex hormone. Estrogens not only have an important role in the regulation of the estrous or menstrual cycle but also control, for example, bone formation, the cardiovascular system, and cognitive functions. Estradiol (E2),

  19. Estrogen and xenoestrogens in breast cancer.

    Science.gov (United States)

    Fernandez, S V; Russo, J

    2010-01-01

    There is growing concern that estrogenic environmental compounds that act as endocrine-disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, specifically 17beta-estradiol, are important factors in the initiation and progression of breast cancer. We have developed an in vitro-in vivo model in which we have demonstrated the carcinogenicity of E2 in human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1, and SNIP were found at different progression stages in this model. The use of this powerful and unique model has provided a tool for exploring whether bisphenol A and butyl benzyl phthalate have relevance in the initiation of breast cancer. These studies provide firsthand evidence that the natural estrogen 17beta-estradiol and xenoestrogenic substances like bisphenol A are able to induce neoplastic transformation in human breast epithelial cells.

  20. Estrogen Effects on Wound Healing

    Directory of Open Access Journals (Sweden)

    Huann-Cheng Horng

    2017-11-01

    Full Text Available Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

  1. Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication.

    Science.gov (United States)

    Chambon, Caroline; Jatzke, Claudia; Wegener, Nico; Gravius, Andreas; Danysz, Wojciech

    2012-12-15

    Benzylquinolone carboxylic acid (BQCA) is a recently described cholinergic muscarinic M(1) receptor positive allosteric modulator having potential as cognitive enhancer in dementia. The present study focused on the characterisation of BQCA's mode of action in relation to positive effects on memory and side-effects in an animal model. To get insight into this mode of action, in vitro receptor potency/left shift experiments in cells stably expressing the rat's M(1) receptor were performed. They revealed an inflection point value of BQCA corresponding to 306nM, and potentiation of the agonist response up to 47-fold in presence of 10μM of BQCA. In vivo, brain microdialysis showed a maximal brain level of 270nM, 40min after i.p. administration at 10mg/kg. Based on in vitro data obtained with this dose, it can be concluded that BQCA reaches brain levels which should potentiate the agonist response about 4-fold. Behavioural data confirmed that BQCA used at 10mg/kg attenuated scopolamine-induced memory deficit in a spontaneous alternation task. Moreover, BQCA showed no side effect at 10mg/kg and above in spontaneous locomotion and salivation tests. The profile of BQCA observed in the present study displays a clear advantage over the M(1)-M(3) agonist cevimeline. The present data show the therapeutic potential of the M(1) receptor positive allosteric modulator BQCA for the treatment of memory deficits observed in Alzheimer's disease. Copyright © 2012. Published by Elsevier B.V.

  2. Targeting Sindbis virus-based vectors to Fc receptor-positive cell types

    International Nuclear Information System (INIS)

    Klimstra, William B.; Williams, Jacqueline C.; Ryman, Kate D.; Heidner, Hans W.

    2005-01-01

    Some viruses display enhanced infection for Fc receptor (FcR)-positive cell types when complexed with virus-specific immunoglobulin (Ig). This process has been termed antibody-dependent enhancement of viral infection (ADE). We reasoned that the mechanism of ADE could be exploited and adapted to target alphavirus-based vectors to FcR-positive cell types. Towards this goal, recombinant Sindbis viruses were constructed that express 1 to 4 immunoglobulin-binding domains of protein L (PpL) as N-terminal extensions of the E2 glycoprotein. PpL is a bacterial protein that binds the variable region of antibody kappa light chains from a range of mammalian species. The recombinant viruses incorporated PpL/E2 fusion proteins into the virion structure and recapitulated the species-specific Ig-binding phenotypes of native PpL. Virions reacted with non-immune serum or purified IgG displayed enhanced binding and ADE for several species-matched FcR-positive murine and human cell lines. ADE required virus expression of a functional PpL Ig-binding domain, and appeared to be FcγR-mediated. Specifically, ADE did not occur with FcγR-negative cells, did not require active complement proteins, and did not occur on FcγR-positive murine cell lines when virions were bound by murine IgG-derived F(ab') 2 fragments

  3. An estrogen-associated dietary pattern and breast cancer risk in the Swedish Mammography Cohort.

    Science.gov (United States)

    Harris, Holly R; Bergkvist, Leif; Wolk, Alicja

    2015-11-01

    High endogenous hormone levels have been associated with breast cancer and dietary factors have the potential to influence breast cancer risk through effects on hormone levels. Dietary patterns derived from reduced rank regression provide a way to identify food groups correlated with hormones and subsequently examine food patterns that may be associated with breast cancer risk. We investigated whether a dietary pattern previously correlated with estradiol and estrone sulfate was associated with breast cancer in the prospective Swedish Mammography Cohort. Among 37,004 primarily postmenopausal women diet was assessed with a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). During 15 years of follow-up 1,603 cases of breast cancer were identified. A higher estrogen dietary pattern score was associated with an increased risk of breast cancer. Women in the highest quartile of estrogen pattern score had a 29% (95% CI = 1.08-1.55) increased risk of breast cancer compared to women in the lowest quartile (p(trend) = 0.006). When the association was examined by estrogen-receptor status, it was only significant for those with estrogen-receptor-positive tumors; however, in the competing risk analysis there were no significant differences in the effect estimates by receptor subtype (p(heterogeneity) = 0.65). Our findings suggest that a dietary pattern associated with higher estrogen levels may increase breast cancer risk. However, whether the influence of this dietary pattern is through a direct effect on estrogen levels deserves further study. © 2015 UICC.

  4. Estrogen Effects on the Mammary Gland in Early and Late Life and Breast Cancer Risk

    Directory of Open Access Journals (Sweden)

    Genevieve Victoria Dall

    2017-05-01

    Full Text Available A woman has an increased risk of breast cancer if her lifelong estrogen exposure is increased due to an early menarche, a late menopause, and/or an absence of childbearing. For decades, it was presumed that the number of years of exposure drove the increased risk, however, recent epidemiological data have shown that early life exposure (young menarche has a more significant effect on cancer risk than late menopause. Thus, rather than the overall exposure it seems that the timing of hormone exposure plays a major role in defining breast cancer risk. In support of this, it is also known that aberrant hormonal exposure prior to puberty can also increase breast cancer risk, yet the elevated estrogen levels during pregnancy decrease breast cancer risk. This suggests that the effects of estrogen on the mammary gland/breast are age-dependent. In this review article, we will discuss the existing epidemiological data linking hormone exposure and estrogen receptor-positive breast cancer risk including menarche, menopause, parity, and aberrant environmental hormone exposure. We will discuss the predominantly rodent generated experimental data that confirm the association with hormone exposure and breast cancer risk, confirming its use as a model system. We will review the work that has been done attempting to define the direct effects of estrogen on the breast, which are beginning to reveal the mechanism of increased cancer risk. We will then conclude with our views on the most pertinent questions to be addressed experimentally in order to explore the relationship between age, estrogen exposure, and breast cancer risk.

  5. Xenoestrogens are potent activators of nongenomic estrogenic responses.

    Science.gov (United States)

    Watson, Cheryl S; Bulayeva, Nataliya N; Wozniak, Ann L; Alyea, Rebecca A

    2007-02-01

    Studies of the nuclear transcriptional regulatory activities of non-physiological estrogens have not explained their actions in mediating endocrine disruption in animals and humans at the low concentrations widespread in the environment. However, xenoestrogens have rarely been tested for their ability to participate in the plethora of nongenomic steroid signaling pathways elucidated over the last several years. Here we review what is known about such responses in comparison to our recent evidence that xenoestrogens can rapidly and potently elicit signaling through nongenomic pathways culminating in functional endpoints. Both estradiol (E(2)) and compounds representing various classes of xenoestrogens (diethylstilbestrol, coumestrol, bisphenol A, DDE, nonylphenol, endosulfan, and dieldrin) act via a membrane version of the estrogen receptor-alpha on pituitary cells, and can provoke Ca(2+) influx via L-type channels, leading to prolactin (PRL) secretion. These hormones and mimetics can also cause the oscillating activation of extracellular regulated kinases (ERKs). However, individual estrogen mimetics differ in their potency and temporal phasing of these activations compared to each other and to E(2). It is perhaps in these ways that they disrupt some endocrine functions when acting in combination with physiological estrogens. Our quantitative assays allow comparison of these outcomes for each mimetic, and let us build a detailed picture of alternative signaling pathway usage. Such an understanding should allow us to determine the estrogenic or antiestrogenic potential of different types of xenoestrogens, and help us to develop strategies for preventing xenoestrogenic disruption of estrogen action in many tissues.

  6. Sulfonation of environmental estrogens by zebrafish cytosolic sulfotransferases.

    Science.gov (United States)

    Ohkimoto, Kei; Sugahara, Takuya; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Yih; Carter, Glendora; Liu, Ming-Cheh

    2003-09-12

    Environmental estrogen-like chemicals are increasingly recognized as a potential hazardous factor for wildlife as well as humans. We have recently embarked on developing a zebrafish model for investigating the role of sulfonation in the metabolism and adverse functioning of environmental estrogens. Here, we report on a systematic investigation of the sulfonation of representative environmental estrogens (bisphenol A, 4-n-octylphenol, 4-n-nolylphenol, diethylstilbestrol, and 17 alpha-ethynylestradiol) by zebrafish cytosolic sulfotransferases (STs). Of the seven enzymes tested, four zebrafish STs (designated ZF ST #2, ZF ST #3, ZF ST #4, and ZF DHEA ST) exhibited differential sulfonating activities toward the five environmental estrogens tested, with ZF ST #3 being more highly active than the other three. It was further demonstrated that bisphenol A, 4-n-octylphenol, and 4-n-nonylphenol exerted concentration-dependent inhibition of the sulfonation of 17 beta-estradiol, implying a potential role of these environmental estrogens in interfering with the sulfonation, and possibly homeostasis, of endogenous estrogens. Kinetic studies revealed that the mechanism underlying the inhibition by bisphenol A or 4-n-nonylphenol to be of the competitive type.

  7. THE ESTROGENS / CHROMIUM INTERACTION IN THE NITRIC OXIDE GENERATION.

    Science.gov (United States)

    Sawicka, Ewa; Piwowar, Agnieszka; Musiala, Tomasz; Dlugosz, Anna

    2017-05-01

    The interaction of estrogens with environmental toxins in free radicals generation: reactive oxygen species (ROS) or reactive nitrogen species (RNS) which participates in cancerogenesis is not yet recognized. Chromium(VI) is widely present in environment. One of its toxicity pathway is free radicals generation. Estrogens have the ability to scavenge free radicals, but may also act as prooxidants. Both chromium(VI) and estrogens are classified by International Agency for Research on Cancer (IARC) as carcinogens, so synergistic effect seems very dangerous. The interaction of chromium and estrogens in ROS generation are partly described but there are no reports on estrogen/chromium interaction on nitric oxide (NO) generation. The aim of the study was to examine the interaction of chromium(VI) and 17-p-estradiol (E2) on NO level in human blood as well as the role of E2 metabolites: 4-hydroxyestradiol (4-OHE2) and 16a-hydroxyestrone (16α-OHE1) in these processes. The NO level was estimated with the diagnostic kit (Nitric Oxide Colorimetric Detection Kit from Arbor Assays) in human blood in vitm. The results showed that Cr(VI) in used concentration (0.5; 1.0 and 5.0 gg/mL) decreases significantly NO level in blood, acting antagonistically to E2 and 4-OHE2. Estrogens (E2, 4-OHE2 and 16α-OHEI) do not protect against inhibiting effect of Cr(VI) on nitric oxide generation in blood because after combined exposure the decreased production of NO in blood was noted. In conclusion, presented results provide the information about the character of estrogen/Cr(VI) interaction in NO level in human blood. It is important knowledge for cardio protected effect e.g., hormone replacement therapy in environmental or occupational exposure to Cr(VI), chromium supplementation, also important for cancer risk evaluation.

  8. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming

    NARCIS (Netherlands)

    Kwakkenbos, Mark J.; Diehl, Sean A.; Yasuda, Etsuko; Bakker, Arjen Q.; van Geelen, Caroline M. M.; Lukens, Michaël; van Bleek, Grada M.; Widjojoatmodjo, Myra N.; Bogers, Willy M. J. M.; Mei, Henrik; Radbruch, Andreas; Scheeren, Ferenc A.; Spits, Hergen; Beaumont, Tim

    The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced

  9. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming

    NARCIS (Netherlands)

    Kwakkenbos, Mark J.; Diehl, Sean A.; Yasuda, Etsuko; Bakker, Arjen Q.; van Geelen, Caroline M. M.; Lukens, Michaël V.; van Bleek, Grada M.; Widjojoatmodjo, Myra N.; Bogers, Willy M. J. M.; Mei, Henrik; Radbruch, Andreas; Scheeren, Ferenc A.; Spits, Hergen; Beaumont, Tim

    2010-01-01

    The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced

  10. Dose-dependent effect of 17 beta-estradiol determined by growth curves and flow cytometric DNA analysis of a human breast carcinoma (T61) grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Vindeløv, L

    1985-01-01

    An estrogen and progesterone receptor-positive human breast carcinoma (T61) grown in nude mice was exposed to 1.0, 0.1, 0.01, and 0.001 mg 17 beta-estradiol. These doses resulted in serum peak concentrations (day 1) of estradiol ranging from 3.5 X 10(-8) to 6.9 X 10(-10) M. The effect...... fraction of polyploid cells. The results suggest that estradiol induces a dose-dependent cell killing effect in the T61 human breast carcinoma. The correlation between the treatment-induced growth delay and the effect on the cell cycle distribution indicates that the changes in the cell cycle...... are a reflection of the estradiol-induced cell destruction. Since no tumor growth stimulation could be observed even at very low serum estradiol concentrations, the T61 human breast carcinoma may represent a new aspect in the study of human breast cancer....

  11. [Estrogens, progestins and blood lipids].

    Science.gov (United States)

    Tikkanen, M J

    1984-01-01

    Progestins and estrogens can affect blood lipids and, as a result, contribute to cardiovascular disease. Since the very first studies, scientists have treated progestins and estrogens separately instead of studying their combined effect. Studies have shown that oral contraceptives (OCs) increase the risk of heart attack and brain hemorrhage. Heart attacks are 3-4 times more likely to occur in women aged 25-49 who are using OCs than those who are not. The risk diminishes after use is discontinued, but women aged 40-49 with a long history of OC use remain twice as prone to heart attacks even after giving up these contraceptives. OCs can cause problems with clotting, resulting in coronary and other arterial complications, increasing atherogenic risk. The effect of steroids on clotting and blood pressure must be studied before it can be determined how cardiovascular disease can be prevented. The author advocates the use of natural and synthetic estrogens in small quantities. He recommends the following in particular: progestins of the pregnal series, desogestrel, and a combination of 19-nortestosterone and estrogen. Synthetic estrogens (mestronol, ethinylestradio) increase high density lipoprotein (HDL) cholesterol levels, and androgens reduce them. Except for desogestrel, currently available progestins are related to androgens. It was discovered in 1977 that progestins in the pregnal series can cause tumors in the breast glands of beagles. Synthetic estrogens increase triglyceride levels by accelerating very low density lipoprotein (VLDL) synthesis. Currently available OCs which contain fewer estrogens, do not affect triglyceride levels to any significant degree. Conjugated estrogens are widely used in Anglo-Saxon countries and can cause hypertriglyceridemia. All other estrogens used to treat symptoms of menopause increase HDL cholesterol and reduce atherogenic LDL cholesterol.

  12. Modulators of androgen and estrogen receptor activity.

    Science.gov (United States)

    Clarke, Bart L; Khosla, Sundeep

    2010-01-01

    This review focuses on significant recent findings regarding modulators of androgen and estrogen receptor activity. Selective androgen receptor modulators (SARMs) interact with androgen receptors (ARs), and selective estrogen receptor modulators (SERMs) interact with estrogen receptors (ERs), with variable tissue selectivity. SERMs, which interact with both ERб and ERв in a tissue-specific manner to produce diverse outcomes in multiple tissues, continue to generate significant interest for clinical application. Development of SARMs for clinical application has been slower to date because of potential adverse effects, but these diverse compounds continue to be investigated for use in disorders in which modulation of the AR is important. SARMs have been investigated mostly at the basic and preclinical level to date, with few human clinical trials published. These compounds have been evaluated mostly for application in different stages of prostate cancer to date, but they hold promise for multiple other applications. Publication of the large STAR and RUTH clinical trials demonstrated that the SERMs tamoxifen and raloxifene have interesting similarities and differences in tissues that contain ERs. Lasofoxifene, bazedoxifene, and arzoxifene are newer SERMs that have been demonstrated in clinical trials to more potently increase bone mineral density and lower serum cholesterol values than tamoxifen or raloxifene. Both SARMs and SERMs hold great promise for therapeutic use in multiple disorders in which tissue-specific effects are mediated by their respective receptors.

  13. Serum estrogen and its metabolites in pregnant women exposed to dioxins and polychlorinated biphenyls (PCBs)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Shuli; Chang, Y.C.; Li, C.M.; Chou, W.L. [National Health Research Insts., Kaohsiung (Taiwan). Div. of Environmental Health and Occupational Medicine; Chao, H.R.; Guo, Y.L. [National Chung Kung Univ., Tainan (Taiwan). Inst. of Environmental Medicine

    2004-09-15

    Dioxins and PCBs are environmental endocrine disruptors that have half-life of 7-10 years in human bodies and have toxicities including carcinogenesis. Studies showed a high estrogen 4-/2- hydroxylation ratio appears to be a marker for neoplasm. The aim is to examine dioxin and PCBs body burden1 in relation to estrogen metabolites and catabolites.

  14. Estrogen and gastrointestinal malignancy.

    LENUS (Irish Health Repository)

    Hogan, A M

    2012-02-01

    The concept that E2 exerts an effect on the gastrointestinal tract is not new and its actions on intestinal mucosa have been investigated for at least three decades. An attempt to consolidate results of these investigations generates more questions than answers, thus suggesting that many unexplored avenues remain and that the full capabilities of this steroid hormone are far from understood. Evidence of its role in esophageal, gastric and gallbladder cancers is confusing and often equivocal. The most compelling evidence regards the protective role conferred by estrogen (or perhaps ERbeta) against the development and proliferation of colon cancer. Not only has the effect been described but also many mechanisms of action have been explored. It is likely that, along with surgery, chemotherapy and radiotherapy, hormonal manipulation will play an integral role in colon cancer management in the very near future.

  15. Skeletal Muscle Estrogen Receptor Activation in Response to Eccentric Exercise Up-Regulates Myogenic-Related Gene Expression Independent of Differing Serum Estradiol Levels Occurring during the Human Menstrual Cycle

    Directory of Open Access Journals (Sweden)

    Mackenzie Haines, Sarah K. McKinley-Barnard, Thomas L. Andre, Josh J. Gann, Paul S. Hwang, Darryn S. Willoughby

    2018-03-01

    Full Text Available This study sought to determine if the differences in serum estradiol we have previously observed to occur during the mid-follicular (MF and mid-luteal (ML phases of the female menstrual cycle could be attributed to estrogen-induced receptor activation and subsequent effects on myogenic-related genes which may otherwise impact muscle regeneration in response to eccentric exercise. Twenty-two physically-active females (20.9 ± 1.4 years, 63.5 ± 9.0 kg, 1.65 ± 0.08 m underwent an eccentric exercise bout of the knee extensors during the MF and ML phases of their 28-day menstrual cycle. Prior to (PRE, at 6 (6HRPOST, and 24 (24HRPOST hours post-exercise for each session, participants had muscle biopsies obtained. Skeletal muscle estradiol and estrogen receptor-α (ER-α content and ER-DNA binding were determined with ELISA. Real-time PCR was used to assess ER-α, Myo-D, and cyclin D1 mRNA expression. Data were analyzed utilizing a 2 x 3 repeated measures univariate analyses of variance (ANOVA for each criterion variable (p ≤ .05. Skeletal muscle estradiol levels were not significantly impacted by either menstrual phase (p > 0.05; however, both ER-α mRNA and protein were significantly increased during MF (p < 0.05. ER-DNA binding and Myo-D mRNA expression increased significantly in both menstrual phases in response to exercise but were not different from one another; however, cyclin D1 mRNA expression was significantly greater during MF. This study demonstrates that skeletal muscle ER-α activation in response to eccentric exercise up-regulates myogenic-related gene expression independent of serum estradiol levels occurring during the human menstrual cycle.

  16. Skeletal Muscle Estrogen Receptor Activation in Response to Eccentric Exercise Up-Regulates Myogenic-Related Gene Expression Independent of Differing Serum Estradiol Levels Occurring during the Human Menstrual Cycle.

    Science.gov (United States)

    Haines, Mackenzie; McKinley-Barnard, Sarah K; Andre, Thomas L; Gann, Josh J; Hwang, Paul S; Willoughby, Darryn S

    2018-03-01

    This study sought to determine if the differences in serum estradiol we have previously observed to occur during the mid-follicular (MF) and mid-luteal (ML) phases of the female menstrual cycle could be attributed to estrogen-induced receptor activation and subsequent effects on myogenic-related genes which may otherwise impact muscle regeneration in response to eccentric exercise. Twenty-two physically-active females (20.9 ± 1.4 years, 63.5 ± 9.0 kg, 1.65 ± 0.08 m) underwent an eccentric exercise bout of the knee extensors during the MF and ML phases of their 28-day menstrual cycle. Prior to (PRE), at 6 (6HRPOST), and 24 (24HRPOST) hours post-exercise for each session, participants had muscle biopsies obtained. Skeletal muscle estradiol and estrogen receptor-α (ER-α) content and ER-DNA binding were determined with ELISA. Real-time PCR was used to assess ER-α, Myo-D, and cyclin D1 mRNA expression. Data were analyzed utilizing a 2 x 3 repeated measures univariate analyses of variance (ANOVA) for each criterion variable (p ≤ .05). Skeletal muscle estradiol levels were not significantly impacted by either menstrual phase (p > 0.05); however, both ER-α mRNA and protein were significantly increased during MF (p < 0.05). ER-DNA binding and Myo-D mRNA expression increased significantly in both menstrual phases in response to exercise but were not different from one another; however, cyclin D1 mRNA expression was significantly greater during MF. This study demonstrates that skeletal muscle ER-α activation in response to eccentric exercise up-regulates myogenic-related gene expression independent of serum estradiol levels occurring during the human menstrual cycle.

  17. Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Jammaz, I. Al, E-mail: jammaz@kfshrc.edu.sa; Al-Otaibi, B.; Amer, S.; Okarvi, S.M.

    2011-10-15

    In an attempt to visualize folate receptors that overexpress on many cancers, [{sup 18}F]-fluorobenzene and pyridinecarbohydrazide-folate/methotrexate conjugates ([{sup 18}F]-1, [{sup 18}F]-2-folates and [{sup 18}F]-8, [{sup 18}F]-9-MTXs) were synthesized by the nucleophilic displacement reactions using ethyl-trimethylammonium-benzoate and pyridinecarboxylate precursors. The intermediates ethyl [{sup 18}F]-fluorinated benzene and pyridine esters were reacted with hydrazine to produce the [{sup 18}F]-fluorobenzene and pyridinecarbohydrazides, followed by coupling with N-hydroxysuccinimide-folate/MTX. Radiochemical yields were greater than 80% (decay corrected), with total synthesis time of less than 45 min. Radiochemical purities were always greater than 97% without high-performance liquid chromatography purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiofluorination of folate derivatives with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that significant amount of the radioconjugates were associated with cell fractions, and in vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and partially by the hepatobiliary systems. Biodistribution studies in nude mice bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable biodistribution profile for [{sup 18}F]-2-folate over the other conjugates. The uptake in the tumors was blocked by excess coinjection of folic acid, suggesting a receptor-mediated process. Micro-positron emission tomography images of nude mice bearing human KB cell line xenografts confirmed these observations. These results demonstrate that [{sup 18}F]-2-folate may be useful as molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response

  18. Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells

    International Nuclear Information System (INIS)

    Hu, Xiaolan; Zhang, Xianqi; Qiu, Shuifeng; Yu, Daihua; Lin, Shuxin

    2010-01-01

    Research highlights: → Salidroside inhibits the growth of human breast cancer cells. → Salidroside induces cell-cycle arrest of human breast cancer cells. → Salidroside induces apoptosis of human breast cancer cell lines. -- Abstract: Recently, salidroside (p-hydroxyphenethyl-β-D-glucoside) has been identified as one of the most potent compounds isolated from plants of the Rhodiola genus used widely in traditional Chinese medicine, but pharmacokinetic data on the compound are unavailable. We were the first to report the cytotoxic effects of salidroside on cancer cell lines derived from different tissues, and we found that human breast cancer MDA-MB-231 cells (estrogen receptor negative) were sensitive to the inhibitory action of low-concentration salidroside. To further investigate the cytotoxic effects of salidroside on breast cancer cells and reveal possible ER-related differences in response to salidroside, we used MDA-MB-231 cells and MCF-7 cells (estrogen receptor-positive) as models to study possible molecular mechanisms; we evaluated the effects of salidroside on cell growth characteristics, such as proliferation, cell cycle duration, and apoptosis, and on the expression of apoptosis-related molecules. Our results demonstrated for the first time that salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells and may be a promising candidate for breast cancer treatment.

  19. Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Xiaolan, E-mail: huxiaolan1998@yahoo.com.cn [Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou (China); Zhang, Xianqi [The 2nd Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou (China); Qiu, Shuifeng [Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou (China); Yu, Daihua; Lin, Shuxin [Fourth Military Medical University, Xi' an (China)

    2010-07-16

    Research highlights: {yields} Salidroside inhibits the growth of human breast cancer cells. {yields} Salidroside induces cell-cycle arrest of human breast cancer cells. {yields} Salidroside induces apoptosis of human breast cancer cell lines. -- Abstract: Recently, salidroside (p-hydroxyphenethyl-{beta}-D-glucoside) has been identified as one of the most potent compounds isolated from plants of the Rhodiola genus used widely in traditional Chinese medicine, but pharmacokinetic data on the compound are unavailable. We were the first to report the cytotoxic effects of salidroside on cancer cell lines derived from different tissues, and we found that human breast cancer MDA-MB-231 cells (estrogen receptor negative) were sensitive to the inhibitory action of low-concentration salidroside. To further investigate the cytotoxic effects of salidroside on breast cancer cells and reveal possible ER-related differences in response to salidroside, we used MDA-MB-231 cells and MCF-7 cells (estrogen receptor-positive) as models to study possible molecular mechanisms; we evaluated the effects of salidroside on cell growth characteristics, such as proliferation, cell cycle duration, and apoptosis, and on the expression of apoptosis-related molecules. Our results demonstrated for the first time that salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells and may be a promising candidate for breast cancer treatment.

  20. Select estrogens within the complex formulation of conjugated equine estrogens (Premarin® are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Brinton Roberta

    2006-03-01

    Full Text Available Abstract Background Results of the Women's Health Initiative Memory Study (WHIMS raised concerns regarding the timing and formulation of hormone interventions. Conjugated equine estrogens (CEE, used as the estrogen therapy in the WHIMS trial, is a complex formulation containing multiple estrogens, including several not secreted by human ovaries, as well as other biologically active steroids. Although the full spectrum of estrogenic components present in CEE has not yet been resolved, 10 estrogens have been identified. In the present study, we sought to determine which estrogenic components, at concentrations commensurate with their plasma levels achieved following a single oral dose of 0.625 mg CEE (the dose used in the WHIMS trial in women, are neuroprotective and whether combinations of those neuroprotective estrogens provide added benefit. Further, we sought, through computer-aided modeling analyses, to investigate the potential correlation of the molecular mechanisms that conferred estrogen neuroprotection with estrogen interactions with the estrogen receptor (ER. Results Cultured basal forebrain neurons were exposed to either β-amyloid25–35 or excitotoxic glutamate with or without pretreatment with estrogens followed by neuroprotection analyses. Three indicators of neuroprotection that rely on different aspects of neuronal damage and viability, LDH release, intracellular ATP level and MTT formazan formation, were used to assess neuroprotective efficacy. Results of these analyses indicate that the estrogens, 17α-estradiol, 17β-estradiol, equilin, 17α-dihydroequilin, equilinen, 17α-dihydroequilenin, 17β-dihydroequilenin, and Δ8,9-dehydroestrone were each significantly neuroprotective in reducing neuronal plasma membrane damage induced by glutamate excitotoxicity. Of these estrogens, 17β-estradiol and Δ8,9-dehydroestrone were effective in protecting neurons against β-amyloid25–35-induced intracellular ATP decline

  1. Estrogen-Cholinergic Interactions: Implications for Cognitive Aging

    Science.gov (United States)

    Newhouse, Paul; Dumas, Julie

    2015-01-01

    While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. PMID:26187712

  2. In vitro modulation of estrogen receptor activity by norfluoxetine.

    Science.gov (United States)

    Lupu, Diana; Pop, Anca; Cherfan, Julien; Kiss, Béla; Loghin, Felicia

    2015-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed for pregnancy and postpartum depression. However, these compounds can cross the placenta and also pass into breast milk, thus reaching the fetus and infant during critical developmental stages, potentially causing adverse effects. Fluoxetine, a widely used SSRI, has been shown to affect (neuro)endocrine signaling in various organisms, including humans. This compound can also interact with estrogen receptors in vitro and cause an estrogen-dependent uterotrophic response in rodents. Consequently, the aim of the present study was to assess if the active metabolite of fluoxetine, namely norfluoxetine (NFLX), shares the same capacity for estrogen receptor interaction. The in vitro (anti)estrogenic activity of norfluoxetine was assessed using a firefly luciferase reporter construct in the T47D-Kbluc breast cancer cell line. These cells express nuclear estrogen receptors (ERs) that can activate the transcription of the luciferase reporter gene upon binding of ER agonists. Light emission was monitored in case of cells exposed to norfluoxetine or mixtures of norfluoxetine-estradiol. Cell viability was assessed using a resazurin-based assay. During individual testing, NFLX was able to induce a significant increase in luciferase activity compared to control, but only at the highest concentration tested (10 μM). In binary mixtures with estradiol (30 pM constant concentration) a significant increase in luminescence was observed at low submicromolar norfluoxetine concentrations compared to estradiol alone. Norfluoxetine can induce estrogenic effects in vitro and can potentiate the activity of estradiol. However, further studies are needed to clarify if these observed estrogenic effects may have detrimental consequences for human exposure.

  3. The Z-isomer of 11{beta}-methoxy-17{alpha}-[{sup 123}I]iodovinylestradiol is a promising radioligand for estrogen receptor imaging in human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rijks, Leonie J. M.; Boer, Gerard J.; Endert, Erik; Bruin, Kora de; Janssen, Anton G. M.; Royen, Eric A. van

    1997-01-01

    The potential of both stereoisomers of 11{beta}-methoxy-17{alpha}-[{sup 123}I]iodovinylestradiol (E- and Z-[{sup 123}I]MIVE) as suitable radioligands for imaging of estrogen receptor(ER)-positive human breast tumours was studied. The 17{alpha}-[{sup 123}I]iodovinylestradiol derivatives were prepared stereospecifically by oxidative radioiododestannylation of the corresponding 17{alpha}-tri-n-butylstannylvinylestradiol precursors. Both isomers of MIVE showed high in vitro affinity for dimethylbenzanthracene-induced rat and fresh human mammary tumour ER, that of Z-MIVE however being manyfold higher than that of E-MIVE. In vivo distribution studies with E- and Z-[{sup 123}I]MIVE in normal and tumour-bearing female rats showed ER-mediated uptake and retention in uterus, ovaries, pituitary, hypothalamus and mammary tumours, again the highest for Z-[{sup 123}I]MIVE. The uterus- and tumour-to-nontarget tissue (fat, muscle) uptake ratios were also highest for Z-[{sup 123}I]MIVE. Additionally, planar whole body imaging of two breast cancer patients 1-2 h after injection of Z-[{sup 123}I]MIVE showed increased focal uptake at known tumour sites. Therefore, we conclude that Z-[{sup 123}I]MIVE is a promising radioligand for the diagnostic imaging of ER in human breast cancer.

  4. EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

    International Nuclear Information System (INIS)

    Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline; Sun, Jianmin; Jögi, Annika; Neumann, Drorit; Rönnstrand, Lars; Påhlman, Sven

    2014-01-01

    Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα + ) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells

  5. EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Sun, Jianmin [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Jögi, Annika [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Neumann, Drorit [Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Rönnstrand, Lars [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Påhlman, Sven, E-mail: sven.pahlman@med.lu.se [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel)

    2014-02-28

    Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα{sup +}) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

  6. Inhibition of aryl hydrocarbon receptor-dependent transcription by resveratrol or kaempferol is independent of estrogen receptor α expression in human breast cancer cells

    Science.gov (United States)

    MacPherson, Laura; Matthews, Jason

    2016-01-01

    Resveratrol and kaempferol are natural chemopreventative agents that are also aryl hydrocarbon receptor (AHR) antagonists and estrogen receptor (ER) agonists. In this study we evaluated the role of ERα in resveratrol- and kaempferol-mediated inhibition of AHR-dependent transcription. Kaempferol or resveratrol inhibited dioxin-induced cytochrome P450 1A1 (CYP1A1) and CYP1B1 expression levels and recruitment of AHR, ERα and co-activators to CYP1A1 and CYP1B1. Both phytochemicals induced the expression and recruitment of ERα to gene amplified in breast cancer 1 (GREB1). RNAi-mediated knockdown of ERα in T-47D cells did not affect the inhibitory action of either phytochemical on AHR activity. Both compounds also inhibited AHR-dependent transcription in ERα-negative MDA-MB-231 and BT-549 breast cancer cells. These data show that ERα does not contribute to the AHR-inhibitory activities of resveratrol and kaempferol. PMID:20846786

  7. Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes.

    Science.gov (United States)

    Pirouzpanah, Saeed; Taleban, Forough-Azam; Mehdipour, Parvin; Sabour, Siamak; Atri, Morteza

    2018-02-14

    The option of endocrine therapy in breast cancer remains conventionally promising. We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, PPR- conditions (Cramer's V= 0.44, PPR (77.1%, PPR expressions (55.6%, PPR- (64.4%, PPR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer.

  8. Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer

    DEFF Research Database (Denmark)

    Alkner, S; Jensen, M-B; Rasmussen, B B

    2017-01-01

    PURPOSE: To evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer. METHOD: AIB1 was analyzed...... with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group's trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs). RESULTS: Forty-six percent of the tumors had a high AIB1 expression. In line...... with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80-100 vs. 1-79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival...

  9. Surgery Should Complement Endocrine Therapy for Elderly Postmenopausal Women with Hormone Receptor-Positive Early-Stage Breast Cancer

    Directory of Open Access Journals (Sweden)

    Olivier Nguyen

    2012-01-01

    Full Text Available Introduction. Endocrine therapy (ET is an integral part of breast cancer (BC treatment with surgical resection remaining the cornerstone of curative treatment. The objective of this study is to compare the survival of elderly postmenopausal women with hormone receptor-positive early-stage BC treated with ET alone, without radiation or chemotherapy, versus ET plus surgery. Materials and Methods. This is a retrospective study based on a prospective database. The medical records of postmenopausal BC patients referred to the surgical oncology service of two hospitals during an 8-year period were reviewed. All patients were to receive ET for a minimum of four months before undergoing any surgery. Results. Fifty-one patients were included and divided in two groups, ET alone and ET plus surgery. At last follow-up in exclusive ET patients (n=28, 39% had stable disease or complete response, 22% had progressive disease, of which 18% died of breast cancer, and 39% died of other causes. In surgical patients (n=23, 78% were disease-free, 9% died of recurrent breast cancer, and 13% died of other causes. Conclusions. These results suggest that surgical resection is beneficial in this group and should be considered, even for patients previously deemed ineligible for surgery.

  10. Clinical implications of recent studies using mTOR inhibitors to treat advanced hormone receptor-positive breast cancer

    International Nuclear Information System (INIS)

    Arena, Francis

    2014-01-01

    Breast cancer is a leading cause of cancer-related death worldwide. Approximately 75% of breast cancer is hormone receptor-positive (HR + ) and is managed with endocrine therapies. However, relapse or disease progression caused by primary or acquired endocrine resistance is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endocrine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when compared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising. Recently, everolimus was approved in combination with exemestane by the US Food and Drug Administration for treating postmenopausal women with advanced HR + breast cancer, based on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted agent approved for combating endocrine resistance

  11. Identification of orexin A- and orexin type 2 receptor-positive cells in the gastrointestinal tract of neonatal dogs

    Directory of Open Access Journals (Sweden)

    C Dall’Aglio

    2009-08-01

    Full Text Available The presence and distribution of cells positive to orexin A (OXA and to orexin type 2 receptor (OX2R were investigated in the gastrointestinal tract of neonatal dogs by means of immunohistochemical techniques. The orexin A-positive cells were identified with some of the endocrine cells in the stomach and in the duodenum; they were both of the open and closed type and were lacking in the large intestine. In the stomach, a large subset of orexin A-positive cells also showed gastrin-like immunoreactivity while, in the duodenum, many of them seemed to store serotonin. The orexin type 2 receptor-positive cells were evidenced all along the gastrointestinal tract examined, also in the large intestine, and they showed the same morphological characteristics as those positive to orexin A. Moreover, the immunohistochemical techniques revealed intense positivity for both orexin A and orexin type 2 receptor in the neurons and fibers of the enteric nervous system. A large subset of orexin A-positive neurons seemed to store substance P.

  12. Prostate-Derived Ets Transcription Factor Overexpression is Associated with Nodal Metastasis, Hormone Receptor Positivity in Invasive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Simon Turcotte

    2007-10-01

    Full Text Available Prostate-derived Ets transcription factor (PDEF has recently been associated with invasive breast cancer, but no expression profile has been defined in clinical specimens. We undertook a comprehensive PDEF transcriptional expression study of 86 breast cancer clinical specimens, several cell lines, normal tissues. PDEF expression profile was analyzed according to standard clinicopathologic parameters, compared with hormonal receptor, HER-2/neu status, to the expression of the new tumor biomarker Dikkopf-1 (DKK1. Wide ranging PDEF overexpression was observed in 74% of tested tumors, at higher levels than the average expression found in normal breasts. High PDEF expression was associated with hormone receptor positivity (P < .001, moderate to good differentiation (less than grade III, P = .01, dissemination to axillary lymph nodes (P = .002. PDEF was an independent risk factor for nodal involvement (multivariate analysis, odds ratio 1.250, P = .002. It was expressed in a different subgroup compared to DKK1-expressing tumors (P < .001. Our data imply that PDEF mRNA expression could be useful in breast cancer molecular staging. Further insights into PDEF functions at the protein level, possible links with hormone receptors biology, bear great potential for new therapeutic avenues.

  13. Lipoxin A4 regulates expression of the estrogen receptor and inhibits 17β-estradiol induced p38 mitogen-activated protein kinase phosphorylation in human endometriotic stromal cells.

    Science.gov (United States)

    Chen, Shuo; Wu, Rong-Feng; Su, Lin; Zhou, Wei-Dong; Zhu, Mao-Bi; Chen, Qiong-Hua

    2014-07-01

    To study the role of lipoxin A4 (LXA4) in endometriosis. Molecular analysis in human samples and primary human endometriotic stromal cells (ESCs). University hospital. Forty-nine premenopausal women (30 patients with endometriosis and 19 controls). Normal and ectopic endometrial biopsies obtained during surgery performed during the proliferative phase of the menstrual cycle; ESCs used for in vitro studies. Levels of LXA4 measured by enzyme-linked immunosorbent assay (ELISA); mRNA levels of the estrogen receptor (ER), progestogen receptor (PR), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR); and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation evaluated by Western blotting. The LXA4 expression level decreased in ectopic tissue as well as ERα and PR, although the expression of ERβ increased in ectopic endometrium compared with the controls. Investigations with correlation analysis revealed the expression of LXA4 was positively correlated with ERα and negatively correlated with ERβ in vivo. Moreover, administering LXA4 could augment ERβ expression in ESCs and inhibit the 17β-estradiol-induced phosphorylation of p38 MAPK very likely through ERβ. Our findings indicate that LXA4 regulates ERβ expression and inhibits 17β-estradiol-induced phosphorylation of p38 MAPK, very likely through ERβ in ESCs. Copyright © 2014. Published by Elsevier Inc.

  14. The Value of Ki67 in Very Young Women with Hormone Receptor-Positive Breast Cancer: Retrospective Analysis of 9,321 Korean Women.

    Science.gov (United States)

    Kim, Jisun; Han, Wonshik; Jung, So-Youn; Park, Yeon Hee; Moon, Hyeong-Gon; Ahn, Soo Kyung; Lee, Jun Woo; Kim, Min Kyoon; Kim, Jong Jin; Lee, Eun Shin; You, Tae Kyung; Kang, Han-Sung; Lee, Eun Sook; Ro, Jungsil; Lee, Jeong Eon; Nam, Seok Jin; Yim, Young-Hyuck; Park, In Ae; Noh, Dong-Young

    2015-10-01

    Young breast cancer patients have a poorer prognosis, especially when their tumors are hormone receptor positive. We analyzed the association between Ki67 and age and the impact of these factors on outcomes in hormone receptor-positive breast cancer. The records of 9,321 hormone receptor-positive invasive breast cancer patients from three large centers were retrospectively reviewed. Each institution separately assayed Ki67 level immunohistochemically. Univariate and multivariate analysis for recurrence-free survival (RFS) was performed on 4,738 patients from a single center. Ki67 level was inversely proportional to age in all three data sets and was significantly higher for younger patients (p Ki67 level (≥10 %) were independent prognostic factors. Although young age was a worse prognostic indicator regardless of HER2 status, Ki67 index was associated with worse prognosis only in HER2-negative patients. When patients were stratified into those with low and high Ki67, young age remained a significant factor for RFS, with hazard ratios in these two Ki67 groups of 2.15 and 2.57, respectively (p Ki67 group had significantly poorer RFS than the older age/high Ki67 group (p Ki67 level was higher in younger patients. However, very young patients had a poorer prognosis regardless of Ki67 level. Unknown biologic factors other than high cell proliferation might play a role in the aggressiveness of hormone receptor-positive breast cancer in very young patients.

  15. Fruits and vegetables intake differentially affects estrogen receptor negative and positive breast cancer incidence rates.

    Science.gov (United States)

    Olsen, Anja; Tjønneland, Anne; Thomsen, Birthe L; Loft, Steffen; Stripp, Connie; Overvad, Kim; Møller, Susanne; Olsen, Jørgen H

    2003-07-01

    Despite intensive research, the evidence for a protective effect of fruits and vegetables on breast cancer risk remains inconclusive. Other risk factors for breast cancer seem to vary with the estrogen receptor status of the breast tumor, and it is thus possible that the inconsistent results regarding a preventive effect of fruits and vegetables are due to lack of controlling for estrogen receptor status. The objective of this study was to investigate the effect of fruit and vegetable intake on postmenopausal breast cancer and explore whether the estrogen receptor status of the tumor modifies this relation. Postmenopausal women (n = 23,798; aged 50-64 y) provided information about diet and established risk factors for breast cancer in the cohort "Diet, Cancer and Health." During follow-up, 425 cases were diagnosed with breast cancer. Associations between intake of fruits and vegetables and the breast cancer rate were analyzed using Cox's regression model. The association for all breast cancers was an incidence rate ratio (IRR) of 1.02 (95% CI, 0.98-1.06) per 100 g/d increment of total intake of fruits, vegetables and juice. For estrogen receptor-positive (ER(+)) breast cancer, a borderline significant increase in the rate was seen, IRR: 1.05 (95% CI, 1.00-1.10), whereas a preventive effect was seen for estrogen receptor-negative (ER(-)) breast cancers, IRR: 0.90 (95% CI, 0.81-0.99). In conclusion, we did not find the overall breast cancer rate to be associated with the intake of fruits and vegetables, but there seemed to be different effects for ER(+) and ER(-) breast cancer.

  16. Effects of antiandrogenic progestins, chlormadinone and cyproterone acetate, and the estrogen 17α-ethinylestradiol (EE2), and their mixtures: Transactivation with human and rainbowfish hormone receptors and transcriptional effects in zebrafish (Danio rerio) eleuthero-embryos

    Energy Technology Data Exchange (ETDEWEB)

    Siegenthaler, Patricia Franziska [University of Applied Sciences and Arts Northwestern Switzerland (FHNW), School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Bain, Peter [Commonwealth Scientific and Industrial Research Organisation (CSIRO), Land and Water Flagship, PMB2, Glen Osmond, 5064 South Australia (Australia); Riva, Francesco [IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri”, Environmental Biomarkers Unit, Department of Environmental Health Sciences, Via La Masa 19, I-20156 Milan (Italy); Fent, Karl, E-mail: karl.fent@fhnw.ch [University of Applied Sciences and Arts Northwestern Switzerland (FHNW), School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Swiss Federal Institute of Technology (ETH Zürich), Institute of Biogeochemistry and Pollution Dynamics, Department of Environmental System Sciences, CH-8092 Zürich (Switzerland)

    2017-01-15

    Highlights: • Agonistic and antagonistic activity of CMA and CPA were assessed in vitro. • CMA and CPA showed different interaction with human and fish receptors. • No progestogenic but antiandrogenic and antiglucocorticoid activity occurred in fish. • CMA and CPA showed transcriptional changes in zebrafish embryos. • Binary mixtures of the progestins with EE2 were assessed in vitro and in vivo. - Abstract: Synthetic progestins act as endocrine disrupters in fish but their risk to the environment is not sufficiently known. Here, we focused on an unexplored antiandrogenic progestin, chlormadinone acetate (CMA), and the antiandrogenic progestin cyproterone acetate (CPA). The aim was to evaluate whether their in vitro interaction with human and rainbowfish (Melanotaenia fluviatilis) sex hormone receptors is similar. Furthermore, we investigated their activity in zebrafish (Danio rerio) eleuthero-embryos. First, we studied agonistic and antagonistic activities of CMA, CPA, and 17α-ethinylestradiol (EE2), in recombinant yeast expressing either the human progesterone (PGR), androgen (AR), or estrogen receptor. The same compounds were also investigated in vitro in a stable transfection cell system expressing rainbowfish nuclear steroid receptors. For human receptors, both progestins exhibited progestogenic, androgenic and antiestrogenic activity with no antiandrogenic or estrogenic activity. In contrast, interactions with rainbowfish receptors showed no progestogenic, but antiandrogenic, antiglucocorticoid, and some antiestrogenic activity. Thus, interaction with and transactivation of human and rainbowfish PGR and AR were distinctly different. Second, we analyzed transcriptional alterations in zebrafish eleuthero‐embryos at 96 and 144 h post fertilization after exposure to CPA, CMA, EE2, and binary mixtures of CMA and CPA with EE2, mimicking the use in oral contraceptives. CMA led to slight down-regulation of the ar transcript, while CPA down-regulated ar

  17. The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

    Science.gov (United States)

    de Mirecki-Garrido, Mercedes; Guerra, Borja; Mateos-Díaz, Carlos; Jiménez-Monzón, Roberto; Díaz-Chico, Nicolás; Díaz-Chico, Juan C.; Fernández-Pérez, Leandro

    2012-01-01

    GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway. Therefore, the interactions of estrogens with GH actions in liver are biologically and clinically relevant because disruption of GH signaling may cause alterations of its endocrine, metabolic, and gender differentiated functions and it could be linked to dramatic impact in liver physiology during development as well as in adulthood. Finally, the interplay of estrogens with GH is relevant because physiological roles these hormones have in human, and the widespread exposition of estrogen or estrogen-related compounds in human. This review highlights the importance of these hormones in liver physiology as well as how estrogens modulate GH actions in liver which will help to improve the clinical use of these hormones. PMID:24281711

  18. 21 CFR 862.1275 - Estrogens (total, nonpregnancy) test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Estrogens (total, nonpregnancy) test system. 862.1275 Section 862.1275 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  19. Estrogenicity and metabolism of prenylated flavonoids and isoflavonoids

    NARCIS (Netherlands)

    Schans, van de M.G.M.

    2015-01-01

      Binding of (prenylated) flavonoids and isoflavonoids to the human estrogen receptors (hERs) might result in beneficial health effects in vivo. To understand structure-activity relationships of prenylated (iso)flavonoids towards the hERs, prenylated (iso)flavonoids were purified from extracts

  20. Original article Expression of Estrogen Alpha and Beta Receptors in ...

    African Journals Online (AJOL)

    mn

    ABSTRACT. Objectives: Estrogen receptors are believed to play a significant role in the pathogenesis of prostate carcinoma (PCa). The aim of this study is to evaluate the expression of ER-α and ER-β in human benign and malignant prostatic tissue. Patients and Methods: The archival materials of 100 prostatic specimens ...

  1. A Chip for Estrogen Receptor Action: Detection of Biomarkers Released by MCF-7 Cells through Estrogenic and Anti-Estrogenic Effects

    Directory of Open Access Journals (Sweden)

    Konstanze Gier

    2017-08-01

    Full Text Available The fluorescence-based multi-analyte chip platform for the analysis of estrogenic and anti-estrogenic substances is a new in vitro tool for the high throughput screening of environmental samples. In contrast to existing tools, the chip investigates the complex action of xenoestrogens in a human cell model by characterizing protein expression. It allows for the quantification of 10 proteins secreted by MCF-7 cells, representing various biological and pathological endpoints of endocrine action and distinguishing between estrogen- and anti-estrogen-dependent secretion of proteins. Distinct protein secretion patterns of the cancer cell line after exposure to known estrogen receptor agonists ß-estradiol, bisphenol A, genistein, and nonylphenol as well as antagonists fulvestrant and tamoxifen demonstrate the potential of the chip. Stimulation of cells with Interleukin-1ß shifts concentrations of low abundant biomarkers towards the working range of the chip. In the non-stimulated cell culture, Matrix Metalloproteinase 9 (MMP-9 and Vascular Endothelial Growth Factor (VEGF show differences upon treatment with antagonists and agonists of the estrogen receptor. In stimulated MCF-7 cells challenged with receptor agonists secretion of Monocyte Chemoattractant Protein (MCP-1, Interleukin-6 (IL-6, Rantes, and Interleukin-8 (IL-8 significantly decreases. In parallel, the proliferating effect of endocrine-disrupting substances in MCF-7 cells is assessed in a proliferation assay based on resazurin. Using ethanol as a solvent for test substances increases the background of proliferation and secretion experiments, while using dimethyl sulfoxide (DMSO does not show any adverse effects. The role of the selected biomarkers in different physiological processes such as cell development, reproduction, cancer, and metabolic syndrome makes the chip an excellent tool for either indicating endocrine-disrupting effects in food and environmental samples, or for screening the

  2. Growth inhibition in response to estrogen withdrawal and tamoxifen therapy of human breast cancer xenografts evaluated by in vivo 31P magnetic resonance spectroscopy, creatine kinase activity, and apoptotic index

    DEFF Research Database (Denmark)

    Kristensen, C A; Kristjansen, P E; Brünner, N

    1995-01-01

    index, and creatine kinase (CK) activity. Tumors of each line were grown in ovariectomized nude mice during stimulation from a s.c. 17 beta-estradiol pellet. At a tumor size of approximately 350 mm3, the pellet was removed from one-half of the animals. The remaining one-half served as controls...... indicate: (a) ZR75-1 and ZR75/LCC-3 xenografts respond differently to estrogen withdrawal and TAM with regard to growth inhibition, 31P magnetic resonance spectroscopy, and CK activity; (b) estrogen withdrawal, but not TAM, induced a decrease in the CK activity of estrogen-dependent tumor tissue, and (c...

  3. Discriminative Stimulus Effects of the GABAB Receptor-Positive Modulator rac-BHFF: Comparison with GABAB Receptor Agonists and Drugs of Abuse

    Science.gov (United States)

    Cheng, Kejun; Rice, Kenner C.

    2013-01-01

    GABAB receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABAB receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors. To examine this, pigeons were trained to discriminate the GABAB receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABAB receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABAB receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABAB receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABAB receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABAB2 subunits of GABAB receptors. At a dose 10-fold lower than the training dose, rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABAB receptor-positive modulators are not identical to those of GABAB receptor agonists. In addition, the results suggest that positive modulation of GABAB receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABAB receptors mediating the effects of baclofen and GHB are not identical. PMID:23275067

  4. Impact of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) co-expression on breast cancer disease characteristics: implications for tumor biology and research.

    Science.gov (United States)

    Alqaisi, Abeer; Chen, Li; Romond, Edward; Chambers, Mara; Stevens, Mark; Pasley, Grace; Awasthi, Mukta; Massarweh, Suleiman

    2014-11-01

    ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.

  5. Role of Estrogen Receptor Signaling in Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    Roy, S.S.; Vadlamudi, R.K.

    2012-01-01

    Metastatic breast cancer is a life-threatening stage of cancer and is the leading cause of death in advanced breast cancer patients. Estrogen signaling and the estrogen receptor (ER) are implicated in breast cancer progression, and the majority of the human breast cancers start out as estrogen dependent. Accumulating evidence suggests that ER signaling is complex, involving coregulatory proteins and extranuclear actions. ER-coregualtory proteins are tightly regulated under normal conditions with miss expression primarily reported in cancer. Deregulation of ER coregualtors or ER extranuclear signaling has potential to promote metastasis in ER-positive breast cancer cells. This review summarizes the emerging role of ER signaling in promoting metastasis of breast cancer cells, discusses the molecular mechanisms by which ER signaling contributes to metastasis, and explores possible therapeutic targets to block ER-driven metastasis

  6. Weight gain in hormone receptor-positive (HR+) early-stage breast cancer: is it menopausal status or something else?

    Science.gov (United States)

    Nyrop, Kirsten A; Deal, Allison M; Lee, Jordan T; Muss, Hyman B; Choi, Seul Ki; Wheless, Amy; Carey, Lisa A; Shachar, Shlomit S

    2018-01-01

    This study investigates weight trajectories in pre- versus postmenopausal breast cancer (BC) survivors diagnosed with hormone receptor-positive tumors, with a specific focus on discerning menopausal status and type of endocrine treatment (ET) as risk factors for weight gain during ET. We conducted a retrospective review of electronic medical records. Descriptive statistics and Chi-squared and t tests were used to compare pre- and postmenopausal women. Chi-squared tests and ANOVA were used for within-group associations between patient characteristics and weight trajectories. Log-binomial regression models were used to estimate relative risk for weight gain. The final sample was 32% premenopausal (n = 140) and 68% postmenopausal (n = 298). Relative risk (RR) for weight gain during ET was highest in women who were premenopausal (RR = 1.29, 1.03-1.52) and had Stage 3 BC (RR = 2.12, 1.59-2.82), mastectomy (RR = 1.49, 1.19-1.88), axillary node dissection (RR = 1.39, 1.11-1.73), and chemotherapy (RR = 1.80, 1.37-2.36). For each kg of weight gained between BC diagnosis and start of ET, and for each additional year of age, RR of gaining weight during ET decreased (RR = 0.98, 0.97-0.99, and RR = 0.99, 0.98-0.99, respectively). Menopausal status and type of ET were not significant predictors of weight gain. In multivariable analysis, only weight loss between BC diagnosis and start of ET was significant. The association of weight loss prior to ET and subsequent substantial weight gain during ET warrants further investigation.

  7. Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.

    Science.gov (United States)

    Regan, Meredith M; Pagani, Olivia; Francis, Prudence A; Fleming, Gini F; Walley, Barbara A; Kammler, Roswitha; Dell'Orto, Patrizia; Russo, Leila; Szőke, János; Doimi, Franco; Villani, Laura; Pizzolitto, Stefano; Öhlschlegel, Christian; Sessa, Fausto; Peg Cámara, Vicente; Rodríguez Peralto, José Luis; MacGrogan, Gaëtan; Colleoni, Marco; Goldhirsch, Aron; Price, Karen N; Coates, Alan S; Gelber, Richard D; Viale, Giuseppe

    2015-11-01

    The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.

  8. Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation.

    Science.gov (United States)

    Benoit, Thibaut; Valera, Marie-Cecile; Fontaine, Coralie; Buscato, Melissa; Lenfant, Francoise; Raymond-Letron, Isabelle; Tremollieres, Florence; Soulie, Michel; Foidart, Jean-Michel; Game, Xavier; Arnal, Jean-Francois

    2017-11-01

    The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  9. Haploinsufficiency of the corepressor of estrogen receptor activity (REA) enhances estrogen receptor function in the mammary gland.

    Science.gov (United States)

    Mussi, Paola; Liao, Lan; Park, Seong-Eun; Ciana, Paolo; Maggi, Adriana; Katzenellenbogen, Benita S; Xu, Jianming; O'Malley, Bert W

    2006-11-07

    Estrogen receptor (ER)-mediated gene expression plays an essential role in mammary gland morphogenesis, function, and carcinogenesis. The repressor of ER activity (REA) is an ER-interactive protein that counterbalances estrogen-induced ER transcriptional activity. Our previous study showed that genetic deletion of both REA alleles resulted in embryonic lethality. This study demonstrates that REA and ERalpha are coexpressed in mammary epithelial cells. REA heterozygous (REA(+/-)) mutant mice exhibit faster mammary ductal elongation in virgin animals, increased lobuloalveolar development during pregnancy, and delayed mammary gland involution after weaning. These morphological phenotypes of REA(+/-) mice are associated with significantly increased cell proliferation and ER transcriptional activities, as indicated by the estrogen response element (ERE)-luciferase reporter in the WT/ERE-Luc and REA(+/-)/ERE-Luc bigenic mice and by the higher expression levels of estrogen-responsive genes such as progesterone receptor and cyclin D1 in the mammary gland. Our analysis also revealed that REA is an important repressor of ER transcriptional activity in the mammary gland under natural, as well as ovariectomized and estrogen-replaced, hormonal conditions. Our results indicate that REA is a physiological modulator of ER function in the mammary gland and that its correct gene dosage is required for maintenance of normal ER activity and normal mammary gland development. Consequently, a reduction or loss of REA function may cause overactivation of ER and increase breast cancer risk in humans.

  10. Comparing predicted estrogen concentrations with measurements in US waters

    International Nuclear Information System (INIS)

    Kostich, Mitch; Flick, Robert; Martinson, John

    2013-01-01

    The range of exposure rates to the steroidal estrogens estrone (E1), beta-estradiol (E2), estriol (E3), and ethinyl estradiol (EE2) in the aquatic environment was investigated by modeling estrogen introduction via municipal wastewater from sewage plants across the US. Model predictions were compared to published measured concentrations. Predictions were congruent with most of the measurements, but a few measurements of E2 and EE2 exceed those that would be expected from the model, despite very conservative model assumptions of no degradation or in-stream dilution. Although some extreme measurements for EE2 may reflect analytical artifacts, remaining data suggest concentrations of E2 and EE2 may reach twice the 99th percentile predicted from the model. The model and bulk of the measurement data both suggest that cumulative exposure rates to humans are consistently low relative to effect levels, but also suggest that fish exposures to E1, E2, and EE2 sometimes substantially exceed chronic no-effect levels. -- Highlights: •Conservatively modeled steroidal estrogen concentrations in ambient water. •Found reasonable agreement between model and published measurements. •Model and measurements agree that risks to humans are remote. •Model and measurements agree significant questions remain about risk to fish. •Need better understanding of temporal variations and their impact on fish. -- Our model and published measurements for estrogens suggest aquatic exposure rates for humans are below potential effect levels, but fish exposure sometimes exceeds published no-effect levels

  11. Biomarker Genes for Detecting Estrogenic Activity of Endocrine Disruptors via Estrogen Receptors

    Directory of Open Access Journals (Sweden)

    Hyun Yang

    2012-02-01

    Full Text Available Endocrine disruptors (EDs are compounds used in various industrial products, drugs, and cosmetics. They can be found in the environment and disturb the endocrine and reproductive systems, resulting in adverse effects to humans and wildlife such as birth defects and developmental disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they intend to have an affinity for steroid hormone receptors and alter hormone-mediated metabolism by binding to these receptors. EDs are therefore a global concern and assays should be developed to efficiently determine whether these compounds are detrimental to biological systems. Diverse experimental methods may help determine the endocrine disrupting potential of EDs and evaluate the adverse effects of a single and/or combination of these reagents. Currently, biomarkers have been employed to objectively measure EDs potency and understand the underlying mechanisms. Further studies are required to develop ideal screening methods and biomarkers to determine EDs potency at environmentally relevant concentrations. In this review, we describe the biomarkers for estrogenicity of EDs identified both in vitro and in vivo, and introduce a biomarker, cabindin-D9k (CaBP-9k, that may be used to assess estrogenic activity of EDs.

  12. Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products.

    Science.gov (United States)

    Myers, Sharon L; Yang, Chun Z; Bittner, George D; Witt, Kristine L; Tice, Raymond R; Baird, Donna D

    2015-05-01

    Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products.

  13. Estrogenic and pregnancy interceptory effects of Achyranthes ...

    African Journals Online (AJOL)

    ... the dose of 200 mg/kg body weight also exhibited estrogenic activity. Histological studies of the uterus were carried out to confirm this estrogenic activity. Keywords: Achyranthes aspera; antifertility; anti-implantation; estrogenic; uterotropic. The African Journal of Traditional, Complementary and Alternative Medicines Vol.

  14. Isoflavones: estrogenic activity, biological effect and bioavailability.

    Science.gov (United States)

    Vitale, Daniela Cristina; Piazza, Cateno; Melilli, Barbara; Drago, Filippo; Salomone, Salvatore

    2013-03-01

    Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones.

  15. Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α

    Directory of Open Access Journals (Sweden)

    Xueyan Chen

    2016-08-01

    Full Text Available Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors.

  16. Molecular imaging provides novel insights on estrogen receptor activity in mouse brain.

    Science.gov (United States)

    Stell, Alessia; Belcredito, Silvia; Ciana, Paolo; Maggi, Adriana

    2008-01-01

    Estrogen receptors have long been known to be expressed in several brain areas in addition to those directly involved in the control of reproductive functions. Investigations in humans and in animal models suggest a strong influence of estrogens on limbic and motor functions, yet the complexity and heterogeneity of neural tissue have limited our approaches to the full understanding of estrogen activity in the central nervous system. The aim of this study was to examine the transcriptional activity of estrogen receptors in the brain of male and female mice. Exploiting the ERE-Luc reporter mouse, we set up a novel, bioluminescence-based technique to study brain estrogen receptor transcriptional activity. Here we show, for the first time, that estrogen receptors are similarly active in male and female brains and that the estrous cycle affects estrogen receptor activity in regions of the central nervous system not known to be associated with reproductive functions. Because of its reproducibility and sensitivity, this novel bioluminescence application stands as a candidate as an innovative methodology for the study and development of drugs targeting brain estrogen receptors.

  17. Molecular Imaging Provides Novel Insights on Estrogen Receptor Activity in Mouse Brain

    Directory of Open Access Journals (Sweden)

    Alessia Stell

    2008-11-01

    Full Text Available Estrogen receptors have long been known to be expressed in several brain areas in addition to those directly involved in the control of reproductive functions. Investigations in humans and in animal models suggest a strong influence of estrogens on limbic and motor functions, yet the complexity and heterogeneity of neural tissue have limited our approaches to the full understanding of estrogen activity in the central nervous system. The aim of this study was to examine the transcriptional activity of estrogen receptors in the brain of male and female mice. Exploiting the ERE-Luc reporter mouse, we set up a novel, bioluminescence-based technique to study brain estrogen receptor transcriptional activity. Here we show, for the first time, that estrogen receptors are similarly active in male and female brains and that the estrous cycle affects estrogen receptor activity in regions of the central nervous system not known to be associated with reproductive functions. Because of its reproducibility and sensitivity, this novel bioluminescence application stands as a candidate as an innovative methodology for the study and development of drugs targeting brain estrogen receptors.

  18. Estrogenic activities in rodent estrogen-free diets.

    Science.gov (United States)

    Ciana, Paolo; Brena, Andrea; Sparaciari, Paolo; Bonetti, Elena; Di Lorenzo, Diego; Maggi, Adriana

    2005-12-01

    Diets lacking soy and alpha-alpha derivatives that are considered to be estrogen-free by standard bioassays (uterotrophic assay and vaginal opening) have been revealed to contain considerable amounts of compounds able to transcriptionally activate the estrogen receptors (ERs) and stimulate luciferase expression in several organs of the ERE-Luc reporter mouse. By molecular imaging, we show that ER activation is present in nonreproductive organs to an extent similar to that observed with the administration of 17beta-estradiol, and it is not influenced by orchiectomy or treatment with an aromatase inhibitor. This, together with the use of a completely synthetic diet, proves that the activation of ERs observed is due to estrogenic compounds present in commercial diets and that it is not a secondary event determined by food consumption and metabolism. The pervasiveness of estrogenic compounds in nature poses the question of how relevant and necessary is the daily ingestion of natural compounds active through the ERs for the maintenance of a correct metabolism in both male and female mammals.

  19. Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma

    Science.gov (United States)

    Rossi, L; Laas, E; Mallon, P; Vincent-Salomon, A; Guinebretiere, J-M; Lerebours, F; Rouzier, R; Pierga, J-Y; Reyal, F

    2015-01-01

    Background: Inconsistencies between mitotic index (MI) and Ki67 measures have been identified in many breast tumour samples. The aim of this study was to describe the prognosis of hormone receptor-positive (HR+) HER2− tumours having discrepant MI and Ki67. Methods: We included a cohort of breast cancer patients initially treated by surgery between 2001 and 2005 in the Institut Curie. Breast cancer-specific survival (BCSS) and disease-free survival (DFS) were analysed according to three proliferation groups: high MI/high Ki67 (MI=3, Ki67>20%), low MI/low Ki67 (MIKi67⩽20%) and discrepant (high MI/low Ki67 or low MI/high Ki67). Results: Among the 1430 patients, 19.6% had discrepant Ki67 and MI, 11.6% had high markers and 68.8% had low markers. The 5-year BCSS was 95.8%, 95% CI (0.93–0.98) in the discrepant group, 99.3%, 95% CI (0.993–0.999) in the low-proliferation group and 91.8%, 95% CI (0.88–0.96) in the high-proliferation group. In multivariate analysis, the survival of the discrepant group was lower than that of the low-proliferation group: BCSS hazard ratio (HR)=3.01 (1.32–6.84; P=0.008) and DFS HR=2.07, 95% CI (1.31–3.26; P=0.002). Among grade 2 tumours in multivariate analysis, DFS of the discrepant group was lower than that of the low MI/low Ki67 group: HR=1.98, 95% CI (1.14–3.46), P=0.02. Regarding BCSS, the obtained results were similar. Conclusion: The prognosis of patients with discrepant MI and Ki67 appears intermediate between that of low MI/low Ki67 and high MI/high Ki67 groups. These markers should be jointly analysed to clarify prognosis. PMID:26379080

  20. Interest in Integrative Medicine Among Postmenopausal Hormone Receptor-Positive Breast Cancer Patients in the EvAluate-TM Study.

    Science.gov (United States)

    Hack, Carolin C; Fasching, Peter A; Fehm, Tanja; de Waal, Johann; Rezai, Mahdi; Baier, Bernd; Baake, Gerold; Kolberg, Hans-Christian; Guggenberger, Martin; Warm, Mathias; Harbeck, Nadia; Wuerstlein, Rachel; Deuker, Jörg-Uwe; Dall, Peter; Richter, Barbara; Wachsmann, Grischa; Brucker, Cosima; Siebers, Jan W; Fersis, Nikos; Kuhn, Thomas; Wolf, Christopher; Vollert, Hans-Walter; Breitbach, Georg-Peter; Janni, Wolfgang; Landthaler, Robert; Kohls, Andreas; Rezek, Daniela; Noesslet, Thomas; Fischer, Gunnar; Henschen, Stefan; Praetz, Thomas; Heyl, Volker; Kühn, Thorsten; Krauss, Thomas; Thomssen, Christoph; Hohn, Andre; Tesch, Hans; Mundhenke, Christoph; Hein, Alexander; Rauh, Claudia; Bayer, Christian M; Jacob, Adib; Schmidt, Katja; Belleville, Erik; Hadji, Peyman; Brucker, Sara Y; Wallwiener, Diethelm; Kümmel, Sherko; Beckmann, Matthias W; Paepke, Daniela

    2017-06-01

    Breast cancer patients often use complementary and alternative medicine, but few prospectively collected data on the topic are available specifically for postmenopausal breast cancer patients. A large prospective study was therefore conducted within a noninterventional study in order to identify the characteristics of patients interested in integrative medicine. The EvAluate-TM study is a prospective, multicenter noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive primary breast cancer. Between 2008 and 2009, 5045 postmenopausal patients were enrolled at 339 certified breast centers in Germany. As part of the data collection process, patients were asked at the baseline about their interest in and information needs relating to integrative medicine. Of the 5045 patients recruited, 3411 responded to the questionnaire on integrative medicine and took part in the analysis, 1583 patients expressed an interest in integrative medicine, and 1828 patients declared no interest. Relevant predictors of interest in integrative medicine were age, body mass index, tumor size, previous chemotherapy, and use of concomitant medications for other medical conditions. Interest in integrative medicine declined highly significantly ( P 65 years, 38.0%). Patients in favor of integrative medicine were significantly less satisfied with the information received about individual treatments and antihormonal therapy. Patients with interest in integrative medicine were more often interested in rehabilitation and fitness, nutritional counseling, and additional support from self-help organizations. These women were mostly interested in receiving information about their disease and integrative medicine from a physician, rather than from other sources. This study shows that a considerable proportion of postmenopausal breast cancer patients are interested in integrative medicine. Information about

  1. Daidzein stimulates osteogenesis facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via estrogen receptor-dependent MEK/ERK and PI3K/Akt activation.

    Science.gov (United States)

    Jin, Xin; Sun, Jing; Yu, Bo; Wang, Yue; Sun, Wei Jia; Yang, Jing; Huang, Su Hui; Xie, Wen Li

    2017-06-01

    Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17β-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms. The results showed that daidzein stimulated cell proliferation by altering cell cycle distribution, promoted cell differentiation by increasing the alkaline phosphatase activity and collagen content, and reduced cell apoptosis associated by up-regulating the expression of Bcl-xL. The above actions of daidzein were prevented by cotreatment with the ER antagonist ICI 182780. Using small interfering RNA technology, we further demonstrated that the effects of daidzein on alkaline phosphatase activity, collagen content, and cell apoptosis are mediated by both ERα and ERβ, whereas the effects on cell proliferation are primarily mediated by ERα. However, the effects of 17β-estradiol on osteoblastic proliferation and survival are mediated by both ER isotypes, and the effects on osteoblastic differentiation are primarily mediated by ERα. The use of specific inhibitors indicated that activation of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) and phosphoinositide 3-kinase/protein kinase B or PKB (PI3K/Akt) signaling pathway at least partially accounts for these effects of daidzein. Taken together, the results indicate that daidzein stimulates osteogenesis through facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via activation of MEK/ERK and PI3K/Akt in an ER-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Imaging of estrogen receptors with radiolabeled-GAP-EDL

    Energy Technology Data Exchange (ETDEWEB)

    Oh, C. S. [The University of Texas M.D. Anderson Cancer Center Houston, Houston (United States); Yang, David J.; Kim, D. E.; Kim, C. K [Wonkwang Univ. College of Medicine, Iksan (Korea, Republic of)

    2007-07-01

    To evaluate the feasibility of using 99mTc-glutamate peptide estradiol(GAP-EDL) in imaging estrogen receptor positive (ER + ) tumor bearing animals. Cellular uptake studies of 99mTc-GAP-EDL was conduct in ER(+) breast cancer cell line (MCF7, 13762 and T47D) in the presence and absence of diethylstilbestrol or tamoxifen. Biodistribution and imaging studies were conducted in rats bearing 13762 breast cancer cells. After posterior limb tumor size reached 8-10 mm, the rats were injected intravenously with 99mTc-GAP-EDL or 99mTc-GAP (10uCi/rat, 10ugm/rat for biodistribution and 300uCi/rat for imaging) and the data were collected at 0.5-4 hrs. 99mTc-DTPA, renal imaging agent, was used for comparison due to its similar carboxylic chelation. To ascertain whether the tumor uptake by 99mTc-GAP-EDL was via an estrogen receptor-mediated process, rats was pretreated with diehystillbestrol (n=3, 10mg/kr, iv) and imaged at 0.5-4.0 hrs. In vitro studies revealed that there was an increased uptake of 99mTc-GAP-EDL compared with that of 99mTc-GAP. There was 10-40% decreased uptake in MCF-7 and T47D cells treated with diethylstilbestrol or tamoxifen compared to untreated 99mTc-GAP-EDL. Western blot analysis showed that there was an ERK2 phosphorylation process in 13762 cells. Biodistribution studies showed that tumor uptake, tumor-to-blood and tumor-to muscle count density ration in 99mTc-GAP-EDL groups were significantly higher than in 99mTc-GAP groups at 4hrs post-administration. Tumor-to muscle ratios at 0.5-4 hrs were 1.67-2.95 and 1.26-1.75 for 99mTc-GAP-EDL and 99mTc-DTPA, respectively. In blocking studies, tumor-to muscle ratios were 1.98-2.39 and 1.21-1.63 for 99mTc-GAP-EDL and blocked groups, respectively. The finding indicate that tumor uptake of 99mTc-GAP-EDL was via an estrogen receptor-mediated process, subsequently involved in MAP kinase (MAPK) activation as indicated by ERK2 phosphorylation. The finding indicate that 99mTc-GAP-EDL is a functional ER(+) imaging agent.

  3. Environmental Estrogens and Breast cancer

    Directory of Open Access Journals (Sweden)

    llmiawati llmiawati

    2014-12-01

    Full Text Available Background: Recent studies revealed that various man-made chemicals disrupting properties with endocrine- contribute in the development of breast cancer.objective: To review the state of the science of the endocrine-disrupting chemicals (EDC and their role in the development of breast cancer.Methods: Key papers on experimental and epidemiologic studies examining the associations between EDC and breast cancer were searched throJgh the Google Sch-olar and pubMedusing Results: EDC effects depend on the level and timing of exposure, with critical window on developmentalstages. Diethylstilbestrol(DES and bispIenolA(BpA aretwo thoroughlystudied environmental estrogenic compounds. Epidemiological studies showed increased breast cancer incident in women exposed to DES during gestation. ExperimentalstuQies revealed that BPA induces architectural and gene expression froRte changes ir i"J"rt r;;;"ry gtand, with the stroma of fetal mammary gland as the primary target. ihe effects of these environmental estrogens are mostly mediated through the estrogen ieceptors a and B. Their exposure may further sensitize the mammary tissuelo the hit or otner carcinogens. Epigenome alteration in the mammary gland has also been implicated in its neoplastic dLvelopre"nt.Conclusions: Fetal and perinatal stages are the critical exposure windows to environmental estrogens and multiple mechanism is irnplicated in the development of breast cancer resulted from this exposure.

  4. Molecular imaging of estrogen receptors

    NARCIS (Netherlands)

    van Kruchten, Michel

    2015-01-01

    For patients with estrogen receptor (ER) positive breast cancer, endocrine therapy plays a major role in both the adjuvant and palliative setting. For adequate treatment decision-making it is crucial to obtain up-to-date information on the ER-status of the tumor(s), since ER-expression is the sole

  5. Presence of estrogenic activity from emission of fossil fuel combustion as detected by a recombinant yeast bioassay

    Science.gov (United States)

    Wang, Jingxian; Wu, Wenzhong; Henkelmann, Bernhard; You, Li; Kettrup, Antonius; Schramm, Karl-Werner

    Estrogenic activities of emission samples generated by fossil fuel combustion were investigated with human estrogen receptor (ER) recombinant yeast bioassay. The results showed that there were weak but clear estrogenic activities in combustion emissions of fossil fuels including coal, petroleum, and diesel. The estrogenic relative potency (RP) of fossil fuel combustion was the highest in petroleum-fired car, followed by coal-fired stove, diesel-fired agrimotor, coal-fired electric power station. On the other hand, the estrogenic relative inductive efficiency (RIE) was the highest in coal-fired stove and coal-fired electric power station, followed by petroleum-fired car and diesel-fired agrimotor. The estrogenic activities in the sub-fractions from chromatographic separation of emitted materials were also determined. The results indicated that different chemical fractions in these complex systems have different estrogenic potencies. The GC/MS analysis of the emission showed that there were many aromatic carbonyls, big molecular alcohol, PAHs and derivatives, and substituted phenolic compounds and derivatives which have been reported as environmental estrogens. The existence of estrogenic substances in fossil fuel combustion demands further investigation of their potential adverse effects on human and on the ecosystem. The magnitude of pollution due to global usage of fossil fuels makes it imperative to understand the issue of fossil fuel-derived endocrine activities and the associated health risks, particularly the aggregated risks stemmed from exposure to toxicants of multiple sources.

  6. A novel color change mechanism for breast cancer biomarker detection: naphthoquinones as specific ligands of human arylamine N-acetyltransferase 1.

    Science.gov (United States)

    Laurieri, Nicola; Egleton, James E; Varney, Amy; Thinnes, Cyrille C; Quevedo, Camilo E; Seden, Peter T; Thompson, Sam; Rodrigues-Lima, Fernando; Dairou, Julien; Dupret, Jean-Marie; Russell, Angela J; Sim, Edith

    2013-01-01

    Human arylamine N-acetyltransferase 1 (hNAT1) has become an attractive potential biomarker for estrogen-receptor-positive breast cancers. We describe here the mechanism of action of a selective non-covalent colorimetric biosensor for the recognition of hNAT1 and its murine homologue, mNat2, over their respective isoenzymes, leading to new opportunities in diagnosis. On interaction with the enzyme, the naphthoquinone probe undergoes an instantaneous and striking visible color change from red to blue. Spectroscopic, chemical, molecular modelling and biochemical studies reported here show that the color change is mediated by selective recognition between the conjugate base of the sulfonamide group within the probe and the conjugate acid of the arginine residue within the active site of both hNAT1 and mNat2. This represents a new mechanism for selective biomarker sensing and may be exploited as a general approach to the specific detection of biomarkers in disease.

  7. Detecting estrogenic activity in water samples withestrogen-sensitive yeast cells using spectrophotometry and fluorescencemicroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Wozei, E.; Holman, H-Y.N.; Hermanowicz, S.W.; Borglin S.

    2006-03-15

    Environmental estrogens are environmental contaminants that can mimic the biological activities of the female hormone estrogen in the endocrine system, i.e. they act as endocrine disrupters. Several substances are reported to have estrogen-like activity or estrogenic activity. These include steroid hormones, synthetic estrogens (xenoestrogens), environmental pollutants and phytoestrogens (plant estrogens). Using the chromogenic substrate ortho-nitrophenyl-{beta}-D-galactopyranoside (ONPG) we show that an estrogen-sensitive yeast strain RMY/ER-ERE, with human estrogen receptor (hER{alpha}) gene and the lacZ gene which encodes the enzyme {beta}-galactosidase, is able to detect estrogenic activity in water samples over a wide range of spiked concentrations of the hormonal estrogen 17{beta}-estradiol (E2). Ortho-nitrophenol (ONP), the yellow product of this assay can be detected using spectrophotometry but requires cell lysis to release the enzyme and allow product formation. We improved this aspect in a fluorogenic assay by using fluorescein di-{beta}-D-galactopyranoside (FDG) as a substrate. The product was visualized using fluorescence microscopy without the need to kill, fix or lyse the cells. We show that in live yeast cells, the uptake of E2 and the subsequent production of {beta}-galactosidase enzyme occur quite rapidly, with maximum enzyme-catalyzed fluorescent product formation evident after about 30 minutes of exposure to E2. The fluorogenic assay was applied to a selection of estrogenic compounds and the Synchrotron-based Fourier transform infrared (SR-FTIR) spectra of the cells obtained to better understand the yeast whole cell response to the compounds. The fluorogenic assay is most sensitive to E2, but the SR-FTIR spectra suggest that the cells respond to all the estrogenic compounds tested even when no fluorescent response was detected. These findings are promising and may shorten the duration of environmental water screening and monitoring regimes using

  8. Effects of 60-Hz fields, estradiol and xenoestrogens on human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Dees, C.; Travis, C. [Oak Ridge National Lab., TN (United States); Garrett, S. [Oak Ridge Institute for Science and Education, Oak Ridge, TN (United States); Henley, D. [Univ. of Tennessee, Knoxville (United States)

    1996-10-01

    If exposure to xenoestrogens or electromagnetic fields (EMFs) such as 60 Hz contributes to the etiology of breast cancer, it is likely that they must stimulate the growth of breast cells, damage genetic material or enhance the effects of other mitogenic or mutagenic agents (co-promotion). Therefore, the ability of xenoestrogens or exposure to 60-Hz fields to stimulate the entry of growth-arrested human breast cancer cells into the cell cycle was determined using cyclin-dependent kinase 2 (Cdk2) activity, synthesis of cyclin D1 and cdc2 activity. Exposure of estrogen receptor-positive MCF-7 or T-47D cells to estrogen and xenoestrogens (DDT and Red No.3) increased Cdk2 and cyclin B1-cdc2 activity and cyclin D1 synthesis. Exposure of breast cancer cells to 12 mG or 1 or 9 G electromagnetic fields at 60 Hz failed to stimulate Cdk2 or cyclin B1-cdc2 activity or cyclin D1 synthesis. Simultaneous co-exposure of cells to 60-Hz fields and chemical promoters did not enhance Cdk2 activation above the levels produced by the chemical promoter alone. Estrogen and xenoestrogens also stimulated binding of the estrogen receptor to the estrogen receptor element but the EMF did not. Phorbol 12-myristate 13-acetate (PMA) induced phosphorylation of p53 and pRb105 in MCF-7 cells, but EMF exposure had no effect. DNA-damaging chemotherapeutic agents and Red Dye No. 3 were found to increase p53 site-specific DNA binding in breast cancer cells, but EMF exposure did not. These studies suggest that estrogen and xenoestrogens stimulate growth-arrested breast cancer cells to enter the growth cycle, but EMF exposure does not. Site-specific p53-DNA binding was increased in MCF-7 cells treated with DNA-damaging agents, but not by EMF exposure. EMF exposure does not appear to act as a promoter or DNA-damaging agent for human breast cancer cells in vitro. 34 refs., 10 figs.

  9. Estrogen receptor-a in the medial amygdala prevents stress-induced elevations in blood pressure in females

    Science.gov (United States)

    Psychological stress contributes to the development of hypertension in humans. The ovarian hormone, estrogen, has been shown to prevent stress-induced pressor responses in females by unknown mechanisms. Here, we showed that the antihypertensive effects of estrogen during stress were blunted in femal...

  10. Validation of T47D-KBluc cell assay for detection of estrogen receptor agonists and antagonists

    Science.gov (United States)

    There is growing concern of exposure to fish, wildlife, and humans to environmental estrogens and their potential impact on reproductive health. Cell-based assays are useful tools to determine the estrogenic activity of chemicals. Confidence in in vitro assay results is strengthe...

  11. Validation of T47D-KBluc cell assay for detection of estrogen receptor agonists and antagonists###

    Science.gov (United States)

    There is growing concern of exposure to fish, wildlife, and humans to environmental estrogens and their potential impact on reproductive health. Cell-based assays are useful tools to determine the estrogenic activity of chemicals. Confidence in in vitro assay results is strengthe...

  12. Comparison of in vivo and in vitro reporter gene assays for short-term screening of estrogenic activity

    NARCIS (Netherlands)

    Legler, J.; Zeinstra, L.M.; Schuitemaker, F.; Lanser, P.H.; Bogerd, J.; Brouwer, A.; Vethaak, A.D.; Voogt, de P.; Murk, A.J.; Burg, van der B.

    2002-01-01

    Functional in vitro and in vivo reporter gene assays have recently been developed for the rapid determination of exposure to (xeno)estrogens. The in vitro estrogen receptor (ER)-mediated chemically activated luciferase gene expression (ER-CALUX) assay uses T47D human breast cancer cells stably

  13. 4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway

    International Nuclear Information System (INIS)

    Lee, Hye-Rim; Choi, Kyung-Chul

    2013-01-01

    Highlights: ► Cathepsins B and D were markedly enhanced by octylphenol (OP) in MCF-7 cells. ► OP may accelerate breast cancer cell growth and cathepsins via ER-mediated signaling. ► Breast cancer cells exposed with OP to mouse model were more aggressive. ► OP can promote metastasis through the amplification of cathepsins B and D via ER-mediated signaling pathway. -- Abstract: Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48 h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10 −6 M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of

  14. Estrogenic plant foods of red colobus monkeys and mountain gorillas in Uganda.

    Science.gov (United States)

    Wasserman, Michael D; Taylor-Gutt, Alexandra; Rothman, Jessica M; Chapman, Colin A; Milton, Katharine; Leitman, Dale C

    2012-05-01

    Phytoestrogens, or naturally occurring estrogen-mimicking compounds, are found in many human plant foods, such as soybeans (Glycine max) and other legumes. Because the consumption of phytoestrogens may result in both health benefits of protecting against estrogen-dependent cancers and reproductive costs of disrupting the developing endocrine system, considerable biomedical research has been focused on the physiological and behavioral effects of these compounds. Despite this interest, little is known about the occurrence of phytoestrogens in the diets of wild primates, nor their likely evolutionary importance. We investigated the prevalence of estrogenic plant foods in the diets of two folivorous primate species, the red colobus monkey (Procolobus rufomitratus) of Kibale National Park and mountain gorilla (Gorilla beringei) of Bwindi Impenetrable National Park, both in Uganda. To examine plant foods for estrogenic activity, we screened 44 plant items (species and part) comprising 78.4% of the diet of red colobus monkeys and 53 plant items comprising 85.2% of the diet of mountain gorillas using transient transfection assays. At least 10.6% of the red colobus diet and 8.8% of the gorilla diet had estrogenic activity. This was mainly the result of the red colobus eating three estrogenic staple foods and the gorillas eating one estrogenic staple food. All estrogenic plants exhibited estrogen receptor (ER) subtype selectivity, as their phytoestrogens activated ERβ, but not ERα. These results demonstrate that estrogenic plant foods are routinely consumed by two folivorous primate species. Phytoestrogens in the wild plant foods of these two species and many other wild primates may have important implications for understanding primate reproductive ecology. Copyright © 2012 Wiley Periodicals, Inc.

  15. Urinary estrogen levels in women on contraceptives in Enugu, South-East Nigeria

    Directory of Open Access Journals (Sweden)

    Ignatius C Maduka

    2012-01-01

    Full Text Available Background: Substantial evidence supports a causal relationship between the risk of human breast cancer and levels of endogenous estrogens. Aim: To evaluate the urinary estrogen of women on contraceptives and also compare the levels in two different classes of contraceptives; hence, the possible predisposition of such women to the risk of breast cancer. Setting and Design: Urinary estrogen level was evaluated in 84 women attending family planning clinic in University of Nigeria Teaching Hospital Enugu, Nigeria, who have been on contraceptive device for 10 years or less (≤10 years. They were aged between 21 and 50 years and were divide into three groups (21-30 years, 31-40 years, and >40 years. The control group consisted of 30 age-matched apparently-healthy women who were not on any contraceptive device. Materials and Methods: Estrogen was analyzed using Ecologenia; Estrogen (E1/E2/E3 microplate enzyme-linked immunosorbent assay (ELISA kit, Batch No. T2GR4, from Japan Envirochemicals Ltd, Japan. Statistical Analysis Used: Significant differences between means were determined by two-tailed Student′s t-test using graph pad prism computer software program. Result: There was a statistically significant increase (P=0.0462, in the mean urinary estrogen level of women on contraceptives when compared with the control. The highest amount of estrogen was excreted by the women in the 21-30 years age group. When the contraceptive devices were divided into two classes of intra-uterine device and oral/injectables, there was no statistical difference (P=0.8112 in the mean urinary estrogen output of the women. Conclusion: The synthetic estrogen content of contraceptive device most probably contributed to the level excreted in the urine. The increased estrogen output observed in women on contraceptive device was not dependent on the class of contraceptive device used.

  16. The expression of Egfl7 in human normal tissues and epithelial tumors.

    Science.gov (United States)

    Fan, Chun; Yang, Lian-Yue; Wu, Fan; Tao, Yi-Ming; Liu, Lin-Sen; Zhang, Jin-Fan; He, Ya-Ning; Tang, Li-Li; Chen, Guo-Dong; Guo, Lei

    2013-04-23

    To investigate the expression of Egfl7 in normal adult human tissues and human epithelial tumors.
 RT-PCR and Western blot were employed to detect Egfl7 expression in normal adult human tissues and 10 human epithelial tumors including hepatocellular carcinoma (HCC), lung cancer, breast cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, malignant glioma, ovarian cancer and renal cancer. Immunohistochemistry and cytoimmunofluorescence were subsequently used to determine the localization of Egfl7 in human epithelial tumor tissues and cell lines. ELISA was also carried out to examine the serum Egfl7 levels in cancer patients. In addition, correlations between Egfl7 expression and clinicopathological features as well as prognosis of HCC and breast cancer were also analyzed on the basis of immunohistochemistry results.
 Egfl7 was differentially expressed in 19 adult human normal tissues and was overexpressed in all 10 human epithelial tumor tissues. The serum Egfl7 level was also significantly elevated in cancer patients. The increased Egfl7 expression in HCC correlated with vein invasion, absence of capsule formation, multiple tumor nodes and poor prognosis. Similarly, upregulation of Egfl7 in breast cancer correlated strongly with TNM stage, lymphatic metastasis, estrogen receptor positivity, Her2 positivity and poor prognosis. 
 Egfl7 is significantly upregulated in human epithelial tumor tissues, suggesting Egfl7 to be a potential biomarker for human epithelial tumors, especially HCC and breast cancer.

  17. Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals

    DEFF Research Database (Denmark)

    Andersen, H R; Andersson, A M; Arnold, S F

    1999-01-01

    , estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17beta++-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7...... cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol...

  18. Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits.

    Directory of Open Access Journals (Sweden)

    Julia K Pinsonneault

    Full Text Available Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36, and in the 3'UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank, allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6. Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004, comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002, psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009, and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004. The first common ESR1 variant (MAF 12-33% across races linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders.

  19. What's New in Estrogen Receptor Action in the Female Reproductive Tract:

    OpenAIRE

    Hewitt, Sylvia C.; Winuthayanon, Wipawee; Korach, Kenneth S.

    2016-01-01

    Estrogen receptor alpha (ERα) is a critical player in development and function of the female reproductive system. Perturbations in ERα response can affect wide-ranging aspects of health in humans as well as in livestock and wildlife. Because of its long-known and broad impact, ERα mechanisms of action continue to be the focus on cutting-edge research efforts. Consequently, novel insights have greatly advanced understanding of every aspect of estrogen signaling. In this review, we attempt to b...

  20. Estrogen enhanced cell-cell signalling in breast cancer cells exposed to targeted irradiation

    International Nuclear Information System (INIS)

    Shao, Chunlin; Folkard, Melvyn; Held, Kathryn D; Prise, Kevin M

    2008-01-01

    Radiation-induced bystander responses, where cells respond to their neighbours being irradiated are being extensively studied. Although evidence shows that bystander responses can be induced in many types of cells, it is not known whether there is a radiation-induced bystander effect in breast cancer cells, where the radiosensitivity may be dependent on the role of the cellular estrogen receptor (ER). This study investigated radiation-induced bystander responses in estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells. The influence of estrogen and anti-estrogen treatments on the bystander response was determined by individually irradiating a fraction of cells within the population with a precise number of helium-3 using a charged particle microbeam. Damage was scored as chromosomal damage measured as micronucleus formation. A bystander response measured as increased yield of micronucleated cells was triggered in both MCF-7 and MDA-MB-231 cells. The contribution of the bystander response to total cell damage in MCF-7 cells was higher than that in MDA-MB-231 cells although the radiosensitivity of MDA-MB-231 was higher than MCF-7. Treatment of cells with 17β-estradiol (E2) increased the radiosensitivity and the bystander response in MCF-7 cells, and the effect was diminished by anti-estrogen tamoxifen (TAM). E2 also increased the level of intracellular reactive oxygen species (ROS) in MCF-7 cells in the absence of radiation. In contrast, E2 and TAM had no influence on the bystander response and ROS levels in MDA-MB-231 cells. Moreover, the treatment of MCF-7 cells with antioxidants eliminated both the E2-induced ROS increase and E2-enhanced bystander response triggered by the microbeam irradiation, which indicates that ROS are involved in the E2-enhanced bystander micronuclei formation after microbeam irradiation. The observation of bystander responses in breast tumour cells may offer new potential targets for radiation

  1. An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

    Directory of Open Access Journals (Sweden)

    Gilders Roger M

    2005-12-01

    Full Text Available Abstract Background In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. Discussion We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. Summary Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation.

  2. Occurrence of estrogenic effects in sewage and industrial wastewaters in Beijing, China

    International Nuclear Information System (INIS)

    Ma Mei; Rao Kaifeng; Wang Zijian

    2007-01-01

    Estrogenic potencies of the effluents or water samples from wastewater treatment plants (WWTPs), industries and hospitals and some receiving rivers in Beijing city were estimated by using a human estrogen receptor recombinant yeast assay. Estrogenic activity of industrial wastewaters was found to range from 0.1 to 13.3 ng EEQ/L and decreased to the range of 0.03-1.6 ng EEQ/L after treatment. Estrogenic activity in WWTP influent ranged from 0.3 to 1.7 ng EEQ/L and decreased to the range of 0.05-0.5 ng EEQ/L after treatment. In the receiving river waters, the estrogenic effect range was 0.1-4.7 ng EEQ/L. These data suggest that treated industrial effluents and WWTP effluents of concern are not the only source of estrogenic pollution in surface waters in Beijing city. EEQ levels in Beijing river water are likely attributable to untreated municipal and industrial wastewaters discharged directly into the river. - Estrogenic activity in Beijing river water is attributed to direct discharges of untreated municipal and industrial wastewaters

  3. The estrogen-injected female mouse: new insight into the etiology of PCOS

    Directory of Open Access Journals (Sweden)

    Freeh Steven M

    2009-05-01

    Full Text Available Abstract Background Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland. Methods, Results and Conclusion A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 ug estrogen at 5–7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We

  4. Nongenomic Signaling Pathways of Estrogen Toxicity

    Science.gov (United States)

    Watson, Cheryl S.; Jeng, Yow-Jiun; Kochukov, Mikhail Y.

    2010-01-01

    Xenoestrogens can affect the healthy functioning of a variety of tissues by acting as potent estrogens via nongenomic signaling pathways or by interfering with those actions of multiple physiological estrogens. Collectively, our and other studies have compared a wide range of estrogenic compounds, including some closely structurally related subgroups. The estrogens that have been studied include environmental contaminants of different subclasses, dietary estrogens, and several prominent physiological metabolites. By comparing the nongenomic signaling and functional responses to these compounds, we have begun to address the structural requirements for their actions through membrane estrogen receptors in the pituitary, in comparison to other tissues, and to gain insights into their typical non-monotonic dose-response behavior. Their multiple inputs into cellular signaling begin processes that eventually integrate at the level of mitogen-activated protein kinase activities to coordinately regulate broad cellular destinies, such as proliferation, apoptosis, or differentiation. PMID:19955490

  5. Control of estrogen receptor ligand binding by Hsp90.

    Science.gov (United States)

    Fliss, A E; Benzeno, S; Rao, J; Caplan, A J

    2000-04-01

    The molecular chaperone Hsp90 interacts with unliganded steroid hormone receptors and regulates their activity. We have analyzed the function of yeast and mammalian Hsp90 in regulating the ability of the human estrogen receptor (ER) to bind ligands in vivo and in vitro. Using the yeast system, we show that the ER expressed in several different hsp82 mutant strains binds reduced amounts of the synthetic estrogen diethylstilbestrol compared to the wild type. This defect in hormone binding occurs without any significant change in the steady state levels of ER protein. To analyze the role of mammalian Hsp90, we synthesized the human ER in rabbit reticulocyte lysates containing geldanamycin, an Hsp90 inhibitor. At low concentrations of geldanamycin we observed reduced levels of hormone binding by the ER. At higher concentrations, we found reduced synthesis of the receptor. These data indicate that Hsp90 functions to maintain the ER in a high affinity hormone-binding conformation.

  6. Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles.

    Science.gov (United States)

    Wagner, Martin; Oehlmann, Jörg

    2009-05-01

    Food consumption is an important route of human exposure to endocrine-disrupting chemicals. So far, this has been demonstrated by exposure modeling or analytical identification of single substances in foodstuff (e.g., phthalates) and human body fluids (e.g., urine and blood). Since the research in this field is focused on few chemicals (and thus missing mixture effects), the overall contamination of edibles with xenohormones is largely unknown. The aim of this study was to assess the integrated estrogenic burden of bottled mineral water as model foodstuff and to characterize the potential sources of the estrogenic contamination. In the present study, we analyzed commercially available mineral water in an in vitro system with the human estrogen receptor alpha and detected estrogenic contamination in 60% of all samples with a maximum activity equivalent to 75.2 ng/l of the natural sex hormone 17beta-estradiol. Furthermore, breeding of the molluskan model Potamopyrgus antipodarum in water bottles made of glass and plastic [polyethylene terephthalate (PET)] resulted in an increased reproductive output of snails cultured in PET bottles. This provides first evidence that substances leaching from plastic food packaging materials act as functional estrogens in vivo. Our results demonstrate a widespread contamination of mineral water with xenoestrogens that partly originates from compounds leaching from the plastic packaging material. These substances possess potent estrogenic activity in vivo in a molluskan sentinel. Overall, the results indicate that a broader range of foodstuff may be contaminated with endocrine disruptors when packed in plastics.

  7. Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells

    Czech Academy of Sciences Publication Activity Database

    Vondráček, Jan; Kozubík, Alois; Machala, M.

    2002-01-01

    Roč. 70, č. 2 (2002), s. 193-201 ISSN 1096-6080 R&D Projects: GA ČR GP525/01/D076; GA MZe QC0194 Institutional research plan: CEZ:AV0Z5004920 Keywords : polycyclic aromatic hydrocarbons * estrogenicity * proliferation Subject RIV: BO - Biophysics Impact factor: 3.367, year: 2002

  8. Estrogen augments shear stress-induced signaling and gene expression in osteoblast-like cells via estrogen receptor-mediated expression of beta1-integrin.

    Science.gov (United States)

    Yeh, Chiuan-Ren; Chiu, Jeng-Jiann; Lee, Chih-I; Lee, Pei-Ling; Shih, Yu-Tsung; Sun, Jui-Sheng; Chien, Shu; Cheng, Cheng-Kung

    2010-03-01

    Estrogen and mechanical forces are positive regulators for osteoblast proliferation and bone formation. We investigated the synergistic effect of estrogen and flow-induced shear stress on signal transduction and gene expression in human osetoblast-like MG63 cells and primary osteoblasts (HOBs) using activations of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) and expressions of c-fos and cyclooxygenase-2 (I) as readouts. Estrogen (17beta-estradiol, 10 nM) and shear stress (12 dyn/cm(2)) alone induced transient phosphorylations of ERK and p38 MAPK in MG63 cells. Pretreating MG63 cells with 17beta-estradiol for 6 hours before shearing augmented these shear-induced MAPK phosphorylations. Western blot and flow cytometric analyses showed that treating MG63 cells with 17beta-estradiol for 6 hrs induced their beta(1)-integrin expression. This estrogen-induction of beta(1)-integrin was inhibited by pretreating the cells with a specific antagonist of estrogen receptor ICI 182,780. Both 17beta-estradiol and shear stress alone induced c-fos and Cox-2 gene expressions in MG63 cells. Pretreating MG63 cells with 17beta-estradiol for 6 hrs augmented the shear-induced c-fos and Cox-2 expressions. The augmented effects of 17beta-estradiol on shear-induced MAPK phosphorylations and c-fos and Cox-2 expressions were inhibited by pretreating the cells with ICI 182,780 or transfecting the cells with beta(1)-specific small interfering RNA. Similar results on the augmented effect of estrogen on shear-induced signaling and gene expression were obtained with HOBs. Our findings provide insights into the mechanism by which estrogen augments shear stress responsiveness of signal transduction and gene expression in bone cells via estrogen receptor-mediated increases in beta(1)-integrin expression. Copyright 2010 American Society for Bone and Mineral Research.

  9. Estrogen Augments Shear Stress–Induced Signaling and Gene Expression in Osteoblast-like Cells via Estrogen Receptor–Mediated Expression of β1-Integrin

    Science.gov (United States)

    Yeh, Chiuan-Ren; Chiu, Jeng-Jiann; Lee, Chih-I; Lee, Pei-Ling; Shih, Yu-Tsung; Sun, Jui-Sheng; Chien, Shu; Cheng, Cheng-Kung

    2010-01-01

    Estrogen and mechanical forces are positive regulators for osteoblast proliferation and bone formation. We investigated the synergistic effect of estrogen and flow-induced shear stress on signal transduction and gene expression in human osetoblast-like MG63 cells and primary osteoblasts (HOBs) using activations of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) and expressions of c-fos and cyclooxygenase-2 (I) as readouts. Estrogen (17β-estradiol, 10 nM) and shear stress (12 dyn/cm2) alone induced transient phosphorylations of ERK and p38 MAPK in MG63 cells. Pretreating MG63 cells with 17β-estradiol for 6 hours before shearing augmented these shear-induced MAPK phosphorylations. Western blot and flow cytometric analyses showed that treating MG63 cells with 17β-estradiol for 6 hrs induced their β1-integrin expression. This estrogen-induction of β1-integrin was inhibited by pretreating the cells with a specific antagonist of estrogen receptor ICI 182,780. Both 17β-estradiol and shear stress alone induced c-fos and Cox-2 gene expressions in MG63 cells. Pretreating MG63 cells with 17β-estradiol for 6 hrs augmented the shear-induced c-fos and Cox-2 expressions. The augmented effects of 17β-estradiol on shear-induced MAPK phosphorylations and c-fos and Cox-2 expressions were inhibited by pretreating the cells with ICI 182,780 or transfecting the cells with β1-specific small interfering RNA. Similar results on the augmented effect of estrogen on shear-induced signaling and gene expression were obtained with HOBs. Our findings provide insights into the mechanism by which estrogen augments shear stress responsiveness of signal transduction and gene expression in bone cells via estrogen receptor–mediated increases in β1-integrin expression. © 2010 American Society for Bone and Mineral Research. PMID:19821775

  10. Estrogenic activity, estrogens, and calcium in runoff post-layer litter application from rainfall simulated events

    Science.gov (United States)

    Estrogens in runoff from fields fertilized with animal wastes have been implicated as endocrine disruptors of fish in recipient surface waters. The goal of this study was to measure estrogenic activity in runoff post-application of animal waste with the greatest potential for estrogenic activity - ...

  11. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    Data.gov (United States)

    U.S. Environmental Protection Agency — Data from a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating using predictive computational...

  12. Genetic Polymorphisms, Estrogens, and Breast Density

    National Research Council Canada - National Science Library

    Maskarinec, Gertraud

    2003-01-01

    .... We have completed two investigations that addressed the following specific aims: 1. To examine the association between polymorphism in genes coding for metabolism and biosynthesis of estrogens...

  13. Estrogens and Cognition: Friends or Foes?

    Science.gov (United States)

    Korol, Donna L.; Pisani, Samantha L.

    2015-01-01

    Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings that show the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. PMID:26149525

  14. [Interactions of insulin and estrogen in the regulation of cell proliferation and carcinogenesis].

    Science.gov (United States)

    Suba, Zsuzsanna; Kásler, Miklós

    2012-01-29

    Equilibrium of sexual steroids and metabolic processes has close correlations. Insulin is a potent regulator of human sexual steroid hormone production and modulates their signals at receptor level. Insulin resistance and excessive insulin production provoke hyperandrogenism and estrogen deficiency in women resulting not only in anovulatory dysfunction but also a high risk for cardiovascular diseases and cancer. Physiologic functions of all female organs have higher estrogen demand as compared with men. In healthy women estrogen predominance against androgens is a favor in their reproductive period, which means a strong defense against insulin resistance and its complications. However, in postmenopausal cases the increasing prevalence of insulin resistance and type-2 diabetes associated with estrogen deficiency and androgen excess, result in a gender specific higher risk for precancerous lesions and cancer as compared with men. Estrogen has beneficial effect on the energy metabolism, glucose homeostasis and on the lipid metabolism of liver and of peripheral tissues as well. A moderate or severe decrease in serum estrogen level enhances the prevalence of insulin resistant states. In premenopausal women long or irregular menstrual cycles are predictors for the risk of insulin resistance and type-2 diabetes. Moreover, in postmenopausal estrogen deficient cases elevated fasting glucose, increased body weight and abdominal fat deposition are often observed progressively with age in correlation with an impaired glucose tolerance. In the rare cases of estrogen deficient men severe type-2 diabetes seems to be a characteristic complication. Upon becoming familiar with the cancer risk of insulin resistance and estrogen deficiency, there would be plenty of possibilities for primary cancer prevention. In patients with cancer the treatment of hormonal and metabolic disturbances may become effective adjuvant therapy.

  15. Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease.

    Science.gov (United States)

    Simpkins, J W; Green, P S; Gridley, K E; Singh, M; de Fiebre, N C; Rajakumar, G

    1997-09-22

    cells from the neurotoxic effects of serum deprivation and hypoglycemia in human neuroblastoma cell lines. We have also observed that 17-alpha-estradiol (alpha-E2), a weak estrogen, shows neuroprotective efficacy in the SK-N-SH cell line at concentrations equivalent to beta-E2. Finally, we have observed that tamoxifen, a classic estrogen antagonist, blocks only one-third of the neuroprotective effects of either alpha-E2 or beta-E2. Collectively, these results indicate that estrogen is behaviorally active in tests of learning/ memory; activates basal forebrain cholinergic neurons and neurotrophin expression; and is neuroprotective for human neuronal cultures. We conclude that estrogen may be a useful therapy for AD and other neurodegenerative diseases.

  16. The application of estrogen receptor-1 mutations' detection through circulating tumor dna in breast cancer

    Directory of Open Access Journals (Sweden)

    Binliang Liu

    2017-01-01

    Full Text Available Breast cancer is the most common cancer in women worldwide. Endocrine therapy is the cornerstone of treatment for patients with hormone receptor-positive advanced breast cancer. Unfortunately, although most patients initially respond to endocrine treatment, they will eventually acquire resistance to endocrine therapy. The mechanisms of endocrine resistance are complicated. In particular, the estrogen receptor-1 (ESR1 mutation has been recognized as an important topic in recent years. Mutation of ESR1 leads to complete aromatase inhibitor resistance and partial resistance to estrogen receptor agonists and antagonists. Therefore, during clinical treatment, it is of great importance to continuously monitor ESR1 mutations before and after endocrine therapy. Conventional tissue biopsies have unavoidable disadvantages, and therefore, the use of circulating tumor DNA (ctDNA has become more prevalent because it is noninvasive and convenient, has excellent sensitivity, and can quickly assess the overall situation of the tumor. The current methods for detecting ctDNA ESR1 mutations mainly include droplet digital polymerase chain reaction and next-generation sequencing techniques. Based on their advantages and disadvantages, we can establish an initial ESR1 mutation monitoring system. However, developing robust methods to monitor ESR1 mutation, detecting endocrine drug resistance, and evaluating prognoses for guiding clinical treatment strategies require long-term exploration. In this review, we will summarize recent concepts and advancements regarding ESR1 mutation monitoring, ctDNA detection technology, and their application in endocrine therapy of breast cancer.

  17. Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling.

    Science.gov (United States)

    Lisse, Thomas S; Hewison, Martin; Adams, John S

    2011-03-01

    Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as "vitamin D or estrogen response element-binding proteins", behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro

    DEFF Research Database (Denmark)

    Andersen, Helle Raun; Vinggaard, Anne; Rasmussen, Thomas Høj

    2002-01-01

    Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides...... to their frequent use in Danish greenhouses. In addition, the metabolite mercaptodimethur sulfoxide, the herbicide tribenuron-methyl, and the organochlorine dieldrin, were included. Several of the pesticides, dieldrin, endosulfan, methiocarb, and fenarimol, acted both as estrogen agonists and androgen antagonists....... Prochloraz reacted as both an estrogen and an androgen antagonist. Furthermore, fenarimol and prochloraz were potent aromatase inhibitors while endosulfan was a weak inhibitor. Hence, these three pesticides possess at least three different ways to potentially disturb sex hormone actions. In addition...

  19. Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals

    DEFF Research Database (Denmark)

    Andersen, H R; Andersson, A M; Arnold, S F

    1999-01-01

    The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites...... cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol...... methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods....

  20. Comparison of Short-Term Estrogenicity Tests for Identification of Hormone-Disrupting Chemicals

    DEFF Research Database (Denmark)

    Andersen, Helle Raun; Andersson, Anna-Maria; Arnold, Steven F.

    1999-01-01

    The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites......, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17β-Estradiol, 17α-ethynyl estradiol, and diethylstilbestrol induced a strong...... in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods....

  1. The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties.

    Science.gov (United States)

    Chadwick, L R; Pauli, G F; Farnsworth, N R

    2006-01-01

    As the population ages, there is an ever-increasing need for therapeutic agents that can be used safely and efficaciously to manage symptoms related to postmenopausal estrogen deficiency. Endogenous estrogens, e.g., 17beta-estradiol, of exogenous mammalian origin, e.g., horses, have long been used to manage such symptoms. There are more than 20 different classes of phytochemicals that have demonstrated affinity for human estrogen receptors in vitro. Some studies on exogenous estrogenic substances of botanical origin (phytoestrogens), such as standardized formulations of plant extracts with in vitro and in vivo estrogenic activity from soy (Glycine max Merill.) and red clover (Trifolium pratense L.), suggest clinical efficacy. Few clinical data for phytoestrogens other than isoflavonoids are available. In an exhaustive review of the literature through 2003, only two clinical trials were identified that were designed to evaluate the effect of hops (Humulus lupulus L.) on symptoms related to menopause. Folkloric, chemical, and biological literature relating primarily to the use of hops for their estrogenic activity, and two human clinical trials, are reviewed.

  2. Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

    Directory of Open Access Journals (Sweden)

    Adrian E. Roitberg

    2008-06-01

    Full Text Available Estrogen receptors (ER are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

  3. Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman

    Directory of Open Access Journals (Sweden)

    Peano Bryan J

    2008-06-01

    Full Text Available Abstract Background Vaginal atrophy (VA is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT. The ovariectomized (OVX rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology. Methods We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17β-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17β-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene. Results A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation. Conclusion At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.

  4. Determination of estrogen and gestagen receptors in breast cancer tissue

    International Nuclear Information System (INIS)

    Boettger, I.; Pabst, H.W.; Meyer-Busche, G.

    1984-01-01

    In the past 2 1/2 years, tumors of 229 patients undergoing treatment at the Department of Surgery and Medical Center, Technical University of Munich, and at the surgical as well as the gynecology units of Staedtisches Krankenhaus Munich-Pasing were examined. In 23 females the menopausal state defied retrospective classification. Estrogen receptor assays (ERA) and gestagen receptor assays (GRA) were done with the dextran-coated charcoal (DCC) technique following the recommendations of the EORTC Receptor Group. Tracers employed included (2,4,6,7- 3 H(N))-estradiol, NEN, for ERA and (17α-methyl- 3 H)-promegestone (R 5020), NEN, for GRA. At a defined cut-off of 20 fmol/mg cytosol protein, the following receptor constellations were found to be present: Postmenopausal women (n=155): ER and GR-negativ: 52%; ER-neg., GR-pos.: 14%; ER-pos., GR-neg.: 30%; ER-pos., GR-pos.,: 4%; ER and/or GR-pos.: 48%. Premenopausal women (n=51): 67%, 4%, 24%, 5% and 33%. A tentative reduction of the cut-off to 10 fmol/mg protein showed no significant changes: Postmenopausal: 48%, 19%, 31%, 2% and 52%; premenopausal: 63%, 8%, 25%, 4% and 37%. It is of interest to note that the receptor-positivity rate is about 20% lower than reported data in the literature. Attention will be drawn to potential underlying factors, such as inappropriate handling during tumor removal, preparation, mailing, storage and mistakes during RRA (homogenization, centrifuging, protein determination as well as components and system handling). As the authors cannot yet present their own clinical results of improved treatment regimens based on the receptor levels due to lengthy statistical analyses and the short follow-up period, recent reports from the literature will be reviewed. (Author)

  5. Glutamic acid ameliorates estrogen deficiency-induced menopausal-like symptoms in ovariectomized mice.

    Science.gov (United States)

    Han, Na-Ra; Kim, Hee-Yun; Yang, Woong Mo; Jeong, Hyun-Ja; Kim, Hyung-Min

    2015-09-01

    Some amino acids are considered alternative therapies for improving menopausal symptoms. Glutamic acid (GA), which is abundant in meats, fish, and protein-rich plant foods, is known to be a neurotransmitter or precursor of γ-aminobutyric acid. Although it is unclear if GA functions in menopausal symptoms, we hypothesized that GA would attenuate estrogen deficiency-induced menopausal symptoms. The objective to test our hypothesis was to examine an estrogenic effect of GA in ovariectomized (OVX) mice, estrogen receptor (ER)-positive human osteoblast-like MG-63 cells, and ER-positive human breast cancer MCF-7 cells. The results demonstrated that administration with GA to mice suppressed body weight gain and vaginal atrophy when compared with the OVX mice. A microcomputed tomographic analysis of the trabecular bone showed increases in bone mineral density, trabecular number, and connectivity density as well as a significant decrease in total porosity of the OVX mice treated with GA. In addition, GA increased serum levels of alkaline phosphatase and estrogen compared with the OVX mice. Furthermore, GA induced proliferation and increased ER-β messenger RNA (mRNA) expression, estrogen response element (ERE) activity, extracellular signal-regulated kinase phosphorylation, and alkaline phosphatase activity in MG-63 cells. In MCF-7 cells, GA also increased proliferation, Ki-67 mRNA expression, ER-β mRNA expression, and ERE activity. Estrogen response element activity increased by GA was inhibited by an estrogen antagonist. Taken together, our data demonstrated that GA has estrogenic and osteogenic activities in OVX mice, MG-63 cells, and MCF-7 cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females

    DEFF Research Database (Denmark)

    Ribas, Vicent; Drew, Brian G; Zhou, Zhenqi

    2016-01-01

    Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we establish...

  7. The ability of PAM50 risk of recurrence score to predict 10-year distant recurrence in hormone receptor-positive postmenopausal women with special histological subtypes

    DEFF Research Database (Denmark)

    Laenkholm, Anne-Vibeke; Jensen, Maj-Britt; Eriksen, Jens Ole

    2018-01-01

    INTRODUCTION: The Prosigna-PAM50 risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR) in hormone receptor-positive breast cancer. Here, we examine the ability of Prosigna for predicting DR at 10 years in a subgroup of postmenop......INTRODUCTION: The Prosigna-PAM50 risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR) in hormone receptor-positive breast cancer. Here, we examine the ability of Prosigna for predicting DR at 10 years in a subgroup......, mucinous, papillary, secretory, tubular, neuroendocrine) who were tested with Prosigna. Fine and Gray models were applied to determine the prognostic value of the Prosigna-PAM50 ROR score for DR special subtypes as compared to IDC. RESULTS: Median follow-up for DR was 9.2 year and for OS 15.2 year. The 10...... of the continuous ROR score with risk of DR for both IDC and the special subtypes (IDC: p PAM50 continuous ROR score added significant prognostic information for 10-year DR in postmenopausal patients with special...

  8. Quantum chemical studies of estrogenic compounds

    Science.gov (United States)

    Quantum chemical methods are potent tools to provide information on the chemical structure and electronic properties of organic molecules. Modern computational chemistry methods have provided a great deal of insight into the binding of estrogenic compounds to estrogenic receptors (ER), an important ...

  9. Estrogen, aging and the cardiovascular system.

    Science.gov (United States)

    Stice, James P; Lee, Jennifer S; Pechenino, Angela S; Knowlton, Anne A

    2009-01-01

    Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFkappaB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone.

  10. Guppy sexual behavior as an effect biomarker of estrogen mimics

    DEFF Research Database (Denmark)

    Bayley, M; Nielsen, J R; Baatrup, E

    1999-01-01

    There is widespread concern that some environmental chemicals can reduce the reproductive capability of humans and wildlife by mimicking natural estrogens and disrupting endocrine function. This potential threat to animal populations posed by xenoestrogens has, hardly surprisingly, been met...... by an intensive global effort to identify and develop biomarkers suitable for screening chemicals for estrogen mimicking capacity. Despite this effort, there are few biomarkers capable of linking exposure to xenoestrogens to impaired reproductive capability. The reproductive success of most animals depends...... strongly on the ability to perform the appropriate sexual behavior. The sexual display of the male guppy is strongly linked to reproductive success and is readily quantified under laboratory conditions. This preliminary study demonstrates that exposure of adult male guppies to water weakly contaminated...

  11. Labeled estrogens as mammary tumor probes

    International Nuclear Information System (INIS)

    Feenstra, A.

    1981-01-01

    In this thesis estrogens labeled with a gamma or positron emitting nuclide, called estrogen-receptor binding radiopharmaceuticals are investigated as mammary tumour probes. The requirements for estrogen-receptor binding radiopharmaceuticals are formulated and the literature on estrogens labeled for this purpose is reviewed. The potential of mercury-197/197m and of carbon-11 as label for estrogen-receptor binding radiopharmaceuticals is investigated. The synthesis of 197 Hg-labeled 4-mercury-estradiol and 2-mercury-estradiol and their properties in vitro and in vivo are described. It appears that though basically carbon-11 labeled compounds are very promising as mammary tumour probes, their achievable specific activity has to be increased. (Auth.)

  12. Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics

    Science.gov (United States)

    Cruz, Gonzalo; Foster, Warren; Paredes, Alfonso; Yi, Kun Don; Uzumcu, Mehmet

    2014-01-01

    Estrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is thought that developmental exposure to environmental estrogens can disrupt neural and reproductive tract development potentially resulting in long-term alterations in neurobehavior and reproductive function. Many chemicals have been shown to have estrogenic activity whereas others affect estrogen production and turnover resulting in disruption of estrogen signaling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on estrogen sensitive target tissues. Hence, alternative mechanisms are thought to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including estrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying disruption of ovarian follicular development. In addition, we discuss how exposure to environmental estrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID:25040227

  13. Assessment of cellular estrogenic activity based on estrogen receptor-mediated reduction of soluble-form catechol-O-methyltransferase (COMT expression in an ELISA-based system.

    Directory of Open Access Journals (Sweden)

    Philip Wing-Lok Ho

    Full Text Available Xenoestrogens are either natural or synthetic compounds that mimic the effects of endogenous estrogen. These compounds, such as bisphenol-A (BPA, and phthalates, are commonly found in plastic wares. Exposure to these compounds poses major risk to human health because of the potential to cause endocrine disruption. There is huge demand for a wide range of chemicals to be assessed for such potential for the sake of public health. Classical in vivo assays for endocrine disruption are comprehensive but time-consuming and require sacrifice of experimental animals. Simple preliminary in vitro screening assays can reduce the time and expense involved. We previously demonstrated that catechol-O-methyltransferase (COMT is transcriptionally regulated by estrogen via estrogen receptor (ER. Therefore, detecting corresponding changes of COMT expression in estrogen-responsive cells may be a useful method to estimate estrogenic effects of various compounds. We developed a novel cell-based ELISA to evaluate cellular response to estrogenicity by reduction of soluble-COMT expression in ER-positive MCF-7 cells exposed to estrogenic compounds. In contrast to various existing methods that only detect bioactivity, this method elucidates direct physiological effect in a living cell in response to a compound. We validated our assay using three well-characterized estrogenic plasticizers - BPA, benzyl butyl phthalate (BBP, and di-n-butyl phthalate (DBP. Cells were exposed to either these plasticizers or 17β-estradiol (E2 in estrogen-depleted medium with or without an ER-antagonist, ICI 182,780, and COMT expression assayed. Exposure to each of these plasticizers (10(-9-10(-7M dose-dependently reduced COMT expression (p<0.05, which was blocked by ICI 182,780. Reduction of COMT expression was readily detectable in cells exposed to picomolar level of E2, comparable to other in vitro assays of similar sensitivity. To satisfy the demand for in vitro assays targeting different

  14. Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients : A nationwide study

    NARCIS (Netherlands)

    Kuijer, A|info:eu-repo/dai/nl/41391951X; Drukker, C A; Elias, S G|info:eu-repo/dai/nl/261632590; Smorenburg, C H; Th Rutgers, E J; Siesling, S; van Dalen, Th

    2016-01-01

    Ten years ago gene-expression profiles were introduced to aid adjuvant chemotherapy decision making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation-wide study the evolution of the proportion of patients with

  15. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

    DEFF Research Database (Denmark)

    Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki

    2016-01-01

    Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC...

  16. Facile screening of potential xenoestrogens by an estrogen receptor-based reusable optical biosensor.

    Science.gov (United States)

    Liu, Lanhua; Zhou, Xiaohong; Lu, Yun; Shan, Didi; Xu, Bi; He, Miao; Shi, Hanchang; Qian, Yi

    2017-11-15

    The apparent increase in hormone-induced cancers and disorders of the reproductive tract has led to a growing demand for new technologies capable of screening xenoestrogens. We reported an estrogen receptor (ER)-based reusable fiber biosensor for facile screening estrogenic compounds in environment. The bioassay is based on the competition of xenoestrogens with 17β-estradiol (E 2 ) for binding to the recombinant receptor of human estrogen receptor α (hERα) protein, leaving E 2 free to bind to fluorophore-labeled anti-E 2 monoclonal antibody. Unbound anti-E 2 antibody then binds to the immobilized E 2 -protein conjugate on the fiber surface, and is detected by fluorescence emission induced by evanescent field. As expected, the stronger estrogenic activity of xenoestrogen would result in the weaker fluorescent signal. Three estrogen-agonist compounds, diethylstilbestrol (DES), 4-n-nonylphenol (NP) and 4-n-octylphenol (OP), were chosen as a paradigm for validation of this assay. The rank order of estrogenic potency determined by this biosensor was DES>OP>NP, which were consistent with the published results in numerous studies. Moreover, the E 2 -protein conjugate modified optical fiber was robust enough for over 300 sensing cycles with the signal recoveries ranging from 90% to 100%. In conclusion, the biosensor is reusable, reliable, portable and amenable to on-line operation, providing a facile, efficient and economical alternative to screen potential xenoestrogens in environment. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Using Fenton Oxidation to Simultaneously Remove Different Estrogens from Cow Manure

    Directory of Open Access Journals (Sweden)

    Minxia Sun

    2016-09-01

    Full Text Available The presence of estrogens in livestock excrement has raised concerns about their potential negative influence on animals and the overall food cycle. This is the first investigation to simultaneously remove estrogens, including estriol (E3, bisphenol A (BPA, diethylstilbestrol (DES, estradiol (E2, and ethinyl estradiol (EE2, from cow manure using a Fenton oxidation technique. Based on the residual concentrations and removal efficiency of estrogens, the Fenton oxidation reaction conditions were optimized as follows: a H2O2 dosage of 2.56 mmol/g, a Fe(II to H2O2 molar ratio of 0.125 M/M, a solid to water mass ratio of 2 g/mL, an initial pH of 3, and a reaction time of 24 h. Under these conditions, the simultaneous removal efficiencies of E3, BPA, DES, E2, and EE2, with initial concentrations in cow manure of 97.40, 96.54, 100.22, 95.01, and 72.49 mg/kg, were 84.9%, 99.5%, 99.1%, 97.8%, and 84.5%, respectively. We clarified the possible Fenton oxidation reaction mechanisms that governed the degradation of estrogens. We concluded that Fenton oxidation technique could be effective for efficient removal of estrogens in livestock excrement. Results are of great importance for cow manure reuse in agricultural management, and can be used to reduce the threat of environmental estrogens to human health and ecological safety.

  18. Using Fenton Oxidation to Simultaneously Remove Different Estrogens from Cow Manure.

    Science.gov (United States)

    Sun, Minxia; Xu, Defu; Ji, Yuefei; Liu, Juan; Ling, Wanting; Li, Shunyao; Chen, Mindong

    2016-09-15

    The presence of estrogens in livestock excrement has raised concerns about their potential negative influence on animals and the overall food cycle. This is the first investigation to simultaneously remove estrogens, including estriol (E3), bisphenol A (BPA), diethylstilbestrol (DES), estradiol (E2), and ethinyl estradiol (EE2), from cow manure using a Fenton oxidation technique. Based on the residual concentrations and removal efficiency of estrogens, the Fenton oxidation reaction conditions were optimized as follows: a H₂O₂ dosage of 2.56 mmol/g, a Fe(II) to H₂O₂ molar ratio of 0.125 M/M, a solid to water mass ratio of 2 g/mL, an initial pH of 3, and a reaction time of 24 h. Under these conditions, the simultaneous removal efficiencies of E3, BPA, DES, E2, and EE2, with initial concentrations in cow manure of 97.40, 96.54, 100.22, 95.01, and 72.49 mg/kg, were 84.9%, 99.5%, 99.1%, 97.8%, and 84.5%, respectively. We clarified the possible Fenton oxidation reaction mechanisms that governed the degradation of estrogens. We concluded that Fenton oxidation technique could be effective for efficient removal of estrogens in livestock excrement. Results are of great importance for cow manure reuse in agricultural management, and can be used to reduce the threat of environmental estrogens to human health and ecological safety.

  19. Toxicity and Estrogenic Endocrine Disrupting Activity of Phthalates and Their Mixtures

    Directory of Open Access Journals (Sweden)

    Xueping Chen

    2014-03-01

    Full Text Available Phthalates, widely used in flexible plastics and consumer products, have become ubiquitous contaminants worldwide. This study evaluated the acute toxicity and estrogenic endocrine disrupting activity of butyl benzyl phthalate (BBP, di(n-butyl phthalate (DBP, bis(2-ethylhexyl phthalate (DEHP, diisodecyl phthalate (DIDP, diisononyl phthalate (DINP, di-n-octyl phthalate (DNOP and their mixtures. Using a 72 h zebrafish embryo toxicity test, the LC50 values of BBP, DBP and a mixture of the six phthalates were found to be 0.72, 0.63 and 0.50 ppm, respectively. The other four phthalates did not cause more than 50% exposed embryo mortality even at their highest soluble concentrations. The typical toxicity symptoms caused by phthalates were death, tail curvature, necrosis, cardio edema and no touch response. Using an estrogen-responsive ChgH-EGFP transgenic medaka (Oryzias melastigma eleutheroembryos based 24 h test, BBP demonstrated estrogenic activity, DBP, DEHP, DINP and the mixture of the six phthalates exhibited enhanced-estrogenic activity and DIDP and DNOP showed no enhanced- or anti-estrogenic activity. These findings highlighted the developmental toxicity of BBP and DBP, and the estrogenic endocrine disrupting activity of BBP, DBP, DEHP and DINP on intact organisms, indicating that the widespread use of these phthalates may cause potential health risks to human beings.

  20. Estrogen

    Science.gov (United States)

    ... pharmacist if you are allergic to aspirin or tartrazine (a food color additive). Ask your pharmacist or ... cause growth to slow or stop early in children who take large doses for a long time. ...

  1. A yeast estrogen screen for examining the relative exposure of cells to natural and xenoestrogens.

    Science.gov (United States)

    Arnold, S F; Robinson, M K; Notides, A C; Guillette, L J; McLachlan, J A

    1996-01-01

    Xenoestrogens, such as o,p'-DDT and octyl phenol (OP), have been associated with reproductive abnormalities in various wildlife species. Xenoestrogens mimic the natural estrogen 17 beta-estradiol and compete for binding to the estrogen receptor. Even though the affinity of o,p'-DDT and OP for the estrogen receptor is approximately 1000-fold lower than 17 beta-estradiol, the actions of xenoestrogens could be enhanced if their bioavailability in serum were greater than 17 beta-estradiol. To test this hypothesis, the yeast estrogen screen (YES) was created by expressing human estrogen receptor (hER) and two estrogen response elements (ERE) linked to the lacZ gene. The beta-galactosidase activity of the YES system was significantly increased after treatment with 17 beta-estradiol or the xenoestrogens diethylstilbestrol (DES), o,p'-DDT, and OP but not with vehicle, antiestrogen ICI 164,384, dexamethasone, or testosterone. To determine whether serum proteins affected the bioavailability of natural estrogens compared to xenoestrogens, albumin, sex hormone binding globulin (SHBG), or charcoal-stripped serum were added to the YES system and beta-galactosidase activity assayed. Albumin and SHBG decreased beta-galactosidase activity in the presence of estradiol to a greater extent than DES, o,p'-DDT, and OP. Human and alligator charcoal-stripped serum were also effective at selectively reducing beta-galactosidase activity in the presence of estradiol compared to xenoestrogens. Human serum was more effective than alligator serum in reducing beta-galactosidase activity in the presence of xenoestrogens, indicating that serum may serve as a biomarker for sensitivity to xenoestrogens. Selective binding of 17 beta-estradiol by proteins in serum indicates that certain xenoestrogens may exert greater estrogenicity than originally predicted. The estrogenic potency of a compound involves its binding affinity, bioavailability in serum, and persistence in the environment. Our data

  2. The pyrethroid metabolites 3-phenoxybenzoic acid and 3-phenoxybenzyl alcohol do not exhibit estrogenic activity in the MCF-7 human breast carcinoma cell line or Sprague-Dawley rats

    International Nuclear Information System (INIS)

    Laffin, Brian; Chavez, Marco; Pine, Michelle

    2010-01-01

    Synthetic pyrethroids are one of the most frequently and widely used class of insecticides, primarily because they have a higher insect to mammalian toxicity ratio than organochlorines or organophosphates. The basic structure of pyrethroids can be characterized as an acid joined to an alcohol by an ester bond. Pyrethroid degradation occurs through either oxidation at one or more sites located in the alcohol or acid moieties or hydrolysis at the central ester bond, the latter reaction being important for mammalian metabolism of most pyrethroids. The primary alcohol liberated from the ester cleavage is hydroxylated to 3-phenoxybenzyl alcohol, which for most pyrethroids is then oxidized to 3-phenoxybenzoic acid. These products may then be conjugated with amino acids, sulfates, sugars, or sugar acids. In vitro studies have suggested that some of the pyrethroids may have estrogenic activity. Interestingly, the chemical structure of specific pyrethroid metabolites indicates that they may be more likely to interact with the estrogen receptor than the parent compounds. Two of the pyrethroid metabolites, 3-phenoxybenzoic acid (3PBA) and 3-phenoxybenzyl alcohol (3PBalc) have been reported to have endocrine activity using a yeast based assay. 3PBAlc exhibited estrogenic activity with reported EC 50 s of 6.67 x 10 -6 and 2 x 10 -5 while 3PBAcid exhibited anti-estrogenic activity with a calculated IC 50 of 6.5 x 10 -5 . To determine if the metabolites were able to cause the same effects in a mammalian system, the estrogen-dependent cell line, MCF-7, was utilized. Cells were treated with 1.0, 10.0 or 100.0 μM concentrations of each metabolite and cytotoxicity was assessed. The two lowest concentrations of both metabolites did not induce cell death and even appeared to increase proliferation over that of the control cells. However, when cellular proliferation was measured using a Coulter counter neither metabolite stimulated proliferation (1.0 nM, 10.0 nM, or 10.0 μM) or

  3. Estrogen-like effects of diet-derived cadmium differ from those of orally administered CdCl(2) in the ERE-luc estrogen reporter mouse model.

    Science.gov (United States)

    Ramachandran, Balaji; Mäkelä, Sari; Cravedi, Jean-Pierre; Berglund, Marika; Håkansson, Helen; Damdimopoulou, Pauliina; Maggi, Adriana

    2011-04-25

    Cadmium (Cd), an environmental and dietary contaminant, has been described to mimic the effects of 17β-estradiol (E(2)) in selected model systems when studied as an inorganic salt. However, inorganic Cd salts do not represent the main form of Cd exposure in general human populations. The aims of this study were to compare the estrogen-like effects and the bioavailability of dietary Cd to inorganic CdCl(2). Adult ovariectomized ERE-luc reporter mice were administered two bread based diets containing different concentrations of Cd (17.57 and 49.22μg/kg, corresponding to oral intakes of 1.8 and 5.1μg/kg body weight (bw) per day, respectively), inorganic CdCl(2) (1μg/kg bw per day by gavage) or E(2) (5μg/kg bw per day pellet) for 21 days. The effects on estrogen signaling were investigated by studying the uterine weights, luciferase activation, and expression of endogenous estrogen target genes. The uterine weight was significantly increased by both CdCl(2) and E(2) but not by the Cd containing diets. All treatments modulated the expression of luciferase and the endogenous estrogen target genes; however, there was no consistent overlap between the responses triggered by the bread diets and the responses stimulated by CdCl(2) or E(2). Oral exposure to Cd was calculated and the concentrations in liver and kidneys quantified to estimate the amount of absorbed Cd retained in tissues. The results suggest significantly lower absorption and/or tissue retention of dietary Cd compared to CdCl(2) following oral exposure. Altogether, our results support previous reports on in vivo estrogenicity of CdCl(2) but do not suggest the same activity for diet bound Cd. This study calls for caution when extrapolating results from pure compound studies (e.g. estrogenicity of CdCl(2)) to dietary exposure scenarios (e.g. estrogenicity of diet bound Cd). Further basic research is needed on the mechanisms of interaction between Cd and the estrogen signaling, biologically active species of

  4. Estrogenic Activities of Food Supplements and Beers as Assessed by a Yeast Bioreporter Assay.

    Science.gov (United States)

    Omoruyi, Iyekhoetin Matthew; Pohjanvirta, Raimo

    2017-10-31

    Mounting evidence of the effects of endocrine-disrupting chemicals (EDCs) in humans has led to assaying a vast array of food items (processed or packaged) as possible sources of human exposure to estrogens. In this study, we investigated the current situation in this respect of different food supplements and beer brands. Eleven food supplements and 24 beer brands were obtained from Helsinki, Finland. Sample preparation was carried out by established methods while estrogenic activities were assessed by a yeast bioluminescent assay, using two recombinant yeast strains (Saccharomyces cerevisiae BMAEREluc/ERα and S. cerevisiae BMA64/luc). All the food supplements as well as 81% of the beer samples tested were found to be estrogenic, with estradiol equivalent concentrations of food supplements and beer brands ranging from 7.5 to 11.5 µg/ml and from below detection limits to 43.6 ng/ml, respectively. The estrogenic activities detected in beer samples were not dependent on the beer's alcoholic content, the country of production, or the size of the production brewery. The results of our study imply that both food supplements and beers can be a significant source of human exposure to estrogens. Therefore, further studies and regular surveillance are warranted.

  5. CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark

    2015-01-01

    To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1......-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox...... proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0...

  6. Prenatal lignan exposures, pregnancy urine estrogen profiles and birth outcomes

    International Nuclear Information System (INIS)

    Tang, Rong; Chen, Minjian; Zhou, Kun; Chen, Daozhen; Yu, Jing; Hu, Weiyue; Song, Ling; Hang, Bo; Wang, Xinru; Xia, Yankai

    2015-01-01

    During pregnancy, human exposure to endogenous estrogens and xenoestrogens (such as lignans) may comprehensively impact the gestational maintenance and fetal growth. We measured the concentrations of 5 lignans and the profile of 13 estrogen metabolites (EMs) in the urine samples of 328 pregnant women and examined their associations with birth outcomes. We found significantly positive associations between gestational age and urinary matairesinol (MAT), enterodiol (END) and enterolactone (ENL), as well as 16-hydroxylation pathway EMs. There were consistently positive relationships between END and the 16-hydroxylation pathway EMs. The positive relationships of MAT, END and ENL exposures with the length of gestation were mainly in the low exposure strata of the levels of these EMs. This study reveals that MAT, END and ENL as well as 16-hydroxylation pathway EMs are associated with birth outcomes, and that there are interactive relationships between lignans and 16-hydroxylation pathway EMs with birth outcomes. - Highlights: • We examined relations between prenatal lignan exposures and birth outcomes. • We examined relations between pregnancy urine estrogen profiles and birth outcomes. • MAT, END and ENL are associated with birth outcomes. • 16-hydroxylation pathway EMs are associated with birth outcomes. • There are interactive relationships between ligans and EMs with birth outcomes. - Prenatal lignan exposures and EM levels were interactively related to birth outcomes

  7. The SEEM: selective estrogen enzyme modulators in breast cancer.

    Science.gov (United States)

    Pasqualini, J R; Ebert, C; Chetrite, G S

    1999-12-01

    Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17 beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In the past years, it has been demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone) as well as tibolone and its metabolites are potent inhibitors of sulfatase and 17 beta-hydroxysteroid dehydrogenase activities. It was also shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of Selective Estrogen Enzyme Modulators (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17 beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase, will provide a new option in the treatment of this disease.

  8. Multiple estrogen receptor subtypes influence ingestive behavior in female rodents.

    Science.gov (United States)

    Santollo, Jessica; Daniels, Derek

    2015-12-01

    Postmenopausal women are at an increased risk of obesity and cardiovascular-related diseases. This is attributable, at least in part, to loss of the ovarian hormone estradiol, which inhibits food and fluid intake in humans and laboratory animal models. Although the hypophagic and anti-dipsogenic effects of estradiol have been well documented for decades, the precise mechanisms underlying these effects are not fully understood. An obvious step toward addressing this open question is identifying which estrogen receptor subtypes are involved and what intracellular processes are involved. This question, however, is complicated not only by the variety of estrogen receptor subtypes that exist, but also because many subtypes have multiple locations of action (i.e. in the nucleus or in the plasma membrane). This review will highlight our current understanding of the roles that specific estrogen receptor subtypes play in mediating estradiol's anorexigenic and anti-dipsogenic effects along with highlighting the many open questions that remain. This review will also describe recent work being performed by our laboratory aimed at answering these open questions. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Prediction of ligand binding affinity and orientation of xenoestrogens to the estrogen receptor by molecular dynamics simulations and the linear interaction energy method

    NARCIS (Netherlands)

    van Lipzig, M.M.H.; ter Laak, A.M.; Jongejan, A.; Vermeulen, N.P.E.; Wamelink, M.M.; Geerke, D.P.; Meerman, J.H.N.

    2004-01-01

    Exposure to environmental estrogens has been proposed as a risk factor for disruption of reproductive development and tumorigenesis of humans and wildlife (McLachlan, J. A.; Korach, K. S.; Newbold, R. R.; Degen, G. H. Diethylstilbestrol and other estrogens in the environment. Fundam. Appl. Toxicol.

  10. Development and application of in vitro and in vivo reporter gene assays for the assessment of (xeno-)estrogenic compounds in the aquatic environment

    NARCIS (Netherlands)

    Legler, J.

    2001-01-01

    In recent years, both scientific and public concern about the possible threat of estrogenic compounds in the environment that may impact the reproduction of humans and wildlife has increased. Many substances have been demonstrated to possess estrogenic potency using in

  11. Antiestrogenic activity of flavnoid phytochemicals mediated via c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha

    Science.gov (United States)

    Flavonoid phytochemicals act as both agonists and antagonists of the human estrogen receptors (ERs). While a number of these compounds act by directly binding to the ER, certain phytochemicals, such as the flavonoid compounds chalcone and flavone, elicit antagonistic effects on estrogen signaling in...

  12. The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

    Science.gov (United States)

    Johänning, Janina; Kröner, Patrick; Thomas, Maria; Zanger, Ulrich M; Nörenberg, Astrid; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud; Schroth, Werner; Mürdter, Thomas E

    2018-03-01

    Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

  13. Sex-dependent anti-stress effect of an α5 subunit containing GABAA receptor positive allosteric modulator

    Directory of Open Access Journals (Sweden)

    Sean C. Piantadosi

    2016-11-01

    Full Text Available Rationale: Current first-line treatments for stress-related disorders such as Major Depressive Disorder (MDD act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted α5-PAM, a positive allosteric modulator selective for α5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS and treated with α5-PAM acutely (30 minutes prior to assessing behavior or chronically before being assessed behaviorally. Results: Acute and chronic α5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as behavioral emotionality across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic α5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to α5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in hippocampus after chronic treatment with α5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusions: We showed that acute and chronic positive modulation of α5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

  14. Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Yen Ling Low

    2010-07-01

    Full Text Available Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global = 0.034 and endometrial (p(global = 0.052 cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global = 0.008 and endometrial cancer (p(global = 0.014. The sub-pathway association was validated in the Finnish sample of breast cancer (p(global = 0.015. Further tumor subty