Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer. Abstract: The estrogen receptor (ER) is a nuclear hormone receptor that regulates a variety of genes which promote both cell proliferation and cell cycle progression. In the clinical setting ER positive breast cancer accounts for approximately 2/3 of all breast cancer diagnoses. Anti-estrogen therapies, such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AI), are the core treatment modalities in patients with ER positive breast cancer. Although a large proportion of patients respond positive to endocrine therapy, resistance to these drug treatments remains an impediment to durable clinical response. Selective estrogen receptor degraders (SERDs) that remove the receptor have been shown to be effective in this setting. We describe the discovery of LSZ102, a potent, orally available SERD found to inhibit ER ...

One-hundred and seventy patients with estrogen receptor positive (≥10 pmol/g protein) advanced breast cancer have been treated in a prospective randomized study either with continuous tamoxifen 30 mg × 1 daily (TAM), or with TAM 30 mg × 1 daily for 8 weeks alternating with medroxyprogesterone acetate 500 mg × 2 daily for 8 weeks (TAM/HD-MPA). The response rate was 62% in the group treated with cyclic TAM/HD-MPA versus 41% in the TAM alone group (p = 0.02). There was no significant difference in duration of remissions or survival.

Introduction- Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and it controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated.. Hypothesis- In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. Here we show that ERRγ provokes cardiac hypertrophy by inducing GATA4 and that its inverse agonist, GSK-5182, prevents cardiac hypertrophy.. Methods and Results- The functional roles of ERRγ in association with development of cardiac hypertrophy were examined in primarily cultured cardiomyocytes, in animal models, and in heart samples from human hypertrophic cardiomyopathy patients. ERRγ expression was increased in hearts obtained from human hypertrophic cardiomyopathy patients and in both agonist-induced cellular models and aortic banding-induced animal models of cardiac hypertrophy. Transgenic overexpression in ...

Despite progress in the management of breast cancer, the molecular underpinnings of clinically aggressive subtypes of the disease are not well-understood. Here, we show that activation of Notch developmental signaling in estrogen receptor (ER)-negative breast cancer cells results in direct transcriptional up-regulation of the apoptosis inhibitor and cell cycle regulator survivin. This response is associated with increased expression of survivin at mitosis, enhanced cell proliferation, and heightened viability at cell division. Conversely, targeting Notch signaling with a peptidyl gamma-secretase inhibitor suppressed survivin levels, induced apoptosis, abolished colony formation in soft agar, and inhibited localized and metastatic tumor growth in mice, without organ or systemic toxicity. In contrast, ER+ breast cancer cells, or various normal cell types, were insensitive to Notch stimulation. Therefore, ER- breast cancer cells become dependent on Notch-survivin signaling for their maintenance, in vivo.

Estrogen and progesterone receptors were measured in cystosols prepared from 32 normal ovaries and 25 benign and 49 malignant ovarian tumors. In normal ovarian tissue, estrogen and progesterone receptors were detected in 22 and 75% of specimens, respectively. Estrogen receptors were present in low concentrations ranging from 2 to 9 fmol/mg cytosol protein. The estrogen receptor content and distribution were similar in benign tumors (20%), but progesterone receptors were significantly decreased in 16% of specimens (P less than 0.001). In malignant ovarian tissues, estrogen receptors were present in 57% of specimens in concentration ranging from 1 to 132 fmol/mg cytosol protein. Of these, 72% of tissues had estrogen-receptor concentrations greater than 10 fmol/mg cytosol protein. The presence of estrogen receptors in ovarian cancer was significantly different from normal ovaries and benign tumor tissues (P less than 0.01). Progesterone receptors were detectable in 29% of ovarian cancer specimens. Estrogen

Triple Negative Breasts Cancer tumor (TNBC) is a heterogeneous disease that predicated on immunohistochemistry (IHC) is estrogen receptor (ER) detrimental, progesterone receptor (PR) detrimental and individual epidermal growth aspect receptor 2 (HER2) detrimental. Triple Negative Breasts Cancer (TNBC) is normally a subtype of breasts cancer that predicated on immunohistochemistry (IHC) is normally estrogens receptor (ER) detrimental, progesterone receptor (PR) detrimental and individual epidermal growth aspect receptor 2 (HER2) detrimental [1]. TNBC is normally seen as a its exclusive molecular profile, intense nature, distinctive metastatic patterns and insufficient targeted therapies. Its estimated that from the world-wide breast cancer tumor burden, around 170,000 situations are TNBC and take into account ~10-20% of intrusive breast malignancies [1,2]. Molecular Profile and IHC Phenotype Breasts cancers are usually categorized into seven subtypes (3): luminal A (ER positive and histologic ...

The Ets-1 transcription factor is a candidate breast cancer oncogene that regulates the expression of genes involved in tumor progression and metastasis. Ets-1 signaling has also been linked to the development of a basal-like breast cancer phenotype. We recently described a nitric oxide (NO)-induced gene signature that is associated with poor disease outcome in estrogen receptor-negative (ER-) breast cancer and contains both stem cell-like and basal-like components. Thus, we examined the role of Ets-1 in NO signaling and NO-induced phenotypes in ER- human breast cancer cells. Promoter region analyses were performed on genes upregulated in inducible nitric oxide synthase (NOS2) high expressing tumors for Ets-binding sites. In vitro mechanisms were examined in human basal-like breast cancer cells lines. NO signaling effects were studied using either forced NOS2 expression or the use of a chemical NO-donor, diethlylenetriamine NONOate (DETANO). Promoter region analysis of genes that are up-regulated in

Estrogen receptor negative (ER(−)) breast cancer is aggressive, responds poorly to current treatments and has a poor prognosis. The NF-κB signaling pathway is implicated in ER(−) tumorigenesis. Aspirin (ASA) is chemopreventive against ER(+) but not for ER(−) breast cancers. Nitric oxide-releasing aspirin (NO-ASA) is a safer ASA where ASA is linked to an NO-releasing moiety through a spacer. In vitro, we investigated anti-proliferation effects of NO-ASA (para- and meta-isomers) against ER(−) breast cancer cells MDA-MB-231 and SK-BR-23, effects on NF-κB signaling, and reactive oxygen species by standard techniques. In vivo, effects of NO-ASA were evaluated in a mouse xenograft model using MDA-MB-231 cells. p-NO-ASA inhibited the growth of MDA-MB-231 and SK-BR-3 cells at 24 h, the respective IC50s were 13 ± 2 and 17 ± 2 μM; ASA had an IC50 of |3000 μM in both cell lines. The IC50s for m-NO-ASA in MDA-MB-231 and SK-BR-3 were 173 ± 15 and 185 ± 12 μM, respectively, therefore, implying p-NO

Title: GPER and ER: Estrogen Receptors with Distinct Biological Roles in Breast Cancer. VOLUME: 11 ISSUE: 4. Author(s):Edward J. Filardo. Affiliation:Rhode Island Hospital, Department of Medicine, 593 Eddy Street, Aldrich Building Rm 708, Providence, RI 02903, USA.. Keywords:Estrogen, G-protein-coupled estrogen receptor (GPER), seven transmembrane receptors, estrogen receptors (ERs), nuclear steroid hormone receptors, tamoxifen, faslodex, epidermal growth factor receptors (EGFRs), aromatase inhibitors, breast cancer. Abstract: Comparative clinical studies indicate that blockade of estrogen biosynthesis by the use of aromatase inhibitors may have benefit over estrogen receptor (ER) antagonism as a strategy for treating breast cancer. One plausible explanation for this idea is that more than one type of estrogen receptor may promote the biological effects of estrogen. Recent findings that G-protein-coupled receptor-30, (GPR30/GPER) promotes specific estrogen binding and manifests plasma ...

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P,5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P,0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and ...

What is Triple Negative Breast Cancer? Triple negative breast cancer is not your normal form of breast cancer. It is often referred to as basal cell cancer because it does not express the three genes normally associated with breast cancer. These genes are estrogen receptor (ER), progesterone receptor (PR), or (HR)2.

TY - JOUR. T1 - Reliability of clinical estrogen receptor assays performed on tumor tissue biopsied from sites previously treated with radiotherapy. AU - Valenstein, Steven L.. AU - Voigt, Walter. AU - Vogel, Charles L.. AU - Thomsen, Sharon. AU - Sugarbaker, Everett V.. AU - Castro, Albert. AU - Gupta, Vicram. AU - Charyulu, Komanduri. PY - 1979/6. Y1 - 1979/6. N2 - The present retrospective analysis was done to determine whether previous radiotherapy to a biopsy site could be a source of false-negative estrogen receptor assays as suggested in earlier reports. The present study population included 56 women who had estrogen receptor assays done on tumor tissue obtained from skin, subcutaneous, or lymph node metastases. Tissue was taken from a previously irradiated area in 14 patients and from an unirradiated area in 42. Fifty-seven percent of the former and 50% of the latter patients had positive estrogen receptor assays, and quantitative levels of estrogen receptor also were comparable between ...

TY - JOUR. T1 - Triple negative breast cancer. T2 - A multi-omics network discovery strategy for candidate targets and driving pathways. AU - Karagoz, Kubra. AU - Sinha, Raghu. AU - Arga, Kazim Yalcin. PY - 2015/2/1. Y1 - 2015/2/1. N2 - Triple negative breast cancer (TNBC) represents approximately 15% of breast cancers and is characterized by lack of expression of both estrogen receptor (ER) and progesterone receptor (PR), together with absence of human epidermal growth factor 2 (HER2). TNBC has attracted considerable attention due to its aggressiveness such as large tumor size, high proliferation rate, and metastasis. The absence of clinically efficient molecular targets is of great concern in treatment of patients with TNBC. In light of the complexity of TNBC, we applied a systematic and integrative transcriptomics and interactomics approach utilizing transcriptional regulatory and protein-protein interaction networks to discover putative transcriptional control mechanisms of TNBC. To this ...

Clinical trial for Stage IB Breast Cancer | Estrogen Receptor-negative Breast Cancer | Stage II Breast Cancer | Triple Negative Breast Cancer | Progesterone Receptor-negative Breast Cancer | Stage IA Breast Cancer , MRI and Mammography Before Surgery in Patients With Stage I-II Breast Cancer

TY - JOUR. T1 - Body mass index, mammographic density, and breast cancer risk by estrogen receptor subtype. AU - Shieh, Yiwey. AU - Scott, Christopher G.. AU - Jensen, Matthew R.. AU - Norman, Aaron D.. AU - Bertrand, Kimberly A.. AU - Pankratz, V. Shane. AU - Brandt, Kathleen R. AU - Visscher, Daniel W. AU - Shepherd, John A.. AU - Tamimi, Rulla M.. AU - Vachon, Celine M. AU - Kerlikowske, Karla. PY - 2019/4/3. Y1 - 2019/4/3. N2 - Background: Obesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status. Methods: We conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study ...

TY - JOUR. T1 - Repression of translation of human estrogen receptor α by G-quadruplex formation. AU - Balkwill, Graham D.. AU - Derecka, Kamila. AU - Garner, Thomas P.. AU - Hodgman, Charlie. AU - Flint, A. P F. AU - Searle, Mark S.. PY - 2009/12/8. Y1 - 2009/12/8. N2 - Tissue-specific expression of the human estrogen receptor α gene (ESR1) is achieved through multiple promoter sequences resulting in various mRNA transcripts encoding a common protein but differing in their 5′-untranslated region (5′-UTR). Many cancers are estrogen-sensitive with neoplastic growth stimulated through the estrogen receptor, a transcription factor that regulates developmental genes. We demonstrate that the human ESR1 gene is rich in potential quadruplex-forming sequences with 3 of 20 identified within exonic regions. In particular,we show using CD, UV, and NMR spectroscopy that a stable DNAG-quadruplex motif is formed within the exon C gene sequence. This motif, which PCR shows is transcribed in normal and ...

The final results are in-and they show that 500 mg of Faslodex® (fulvestrant) provides a significant advantage in overall survival compared to 250 mg of the drug in postmenopausal women with locally advanced or metastatic estrogen receptor-positive breast cancer recurring or progressing after prior endocrine therapy. The results were published online in the Journal of the National Cancer Institute.. Each year roughly 200,000 U.S. women are diagnosed with breast cancer. Many of these breast cancers will be hormone receptor-positive, meaning that they are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Treatment of hormone receptor-positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen.. Faslodex-a type of hormonal therapy known as an estrogen receptor antagonist-blocks the actions of estrogen. Its used for the treatment of metastatic, hormone receptor-positive breast cancer in postmenopausal women who experience ...

摘要Estrogen is well known to have a modulatory role on gastrointestinal tract, particularly through its interaction with nuclear estrogen receptors (ERs), alpha and beta (ERα/β). Recent functional studies also indicate that estrogen can activate a G-protein coupled estrogen receptor, GPR30, or GPER1. The present study was designed to identify either the presence or absence of nuclear ERs and GPR30 in the myenteric plexus of the stomach, duodenum, jejunum, ileum and colon of female and male mice. Immunofluorescence staining revealed a high expression of GPR30 in the cytoplasm but not within the nucleus of enteric neurons in female and male mice. ERβ localization was similar to GPR30, where it was expressed in cytoplasm of enteric neurons, but was absent from nuclei, opening up the possibility that ERβ and GPR30 might work together to manifest estrogenic effects. Comparatively, ERα was mainly located in the nuclei of enteric neurons. ERα, ERβ and GPR30 were also expressed in the ...

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Cheung CP, Yu S, Wong KB, Chan LW, Lai FM, Wang X, Suetsugi M, Chen S, Chan FL (Mar 2005). Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. The Journal of Clinical Endocrinology and Metabolism. 90 (3): 1830-44. doi:10.1210/jc.2004-1421. PMID 15598686 ...

In this follow-up study of African American women, oral contraceptive use was more strongly associated with an increased risk of ER−PR− breast cancer than of ER+PR+ breast cancer. The incidence of ER−PR− breast cancer increased significantly among recent users as the duration of use increased, with the largest increase (2.5-fold) among recent users whose duration of use was 10 or more years. However, there were some inconsistencies in that the incidence of ER−PR− cancer was also significantly increased for some shorter-duration and nonrecent categories of use. For ER+PR+ cancer, results were null for most categories of interval since last use and duration but there was a significant increase (1.66-fold) for recent users with 10 or more years of use. Results for ER+PR− tumors were null, but the numbers were small.. The present results strengthen the evidence that there is a stronger association of oral contraceptive use with ER− cancer than with ER+ cancer (32). In several ...

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that is characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) overexpression. The TNBC subtype constitutes approximately 10%-20% of all breast cancers, but has no effective molecular targeted therapies. Previous meta-analysis of gene expression profiles of 587 TNBC cases from 21 studies demonstrated high expression of Wnt signaling pathway-associated genes in basal-like 2 and mesenchymal subtypes of TNBC. In this study, we investigated the potential of Wnt pathway inhibitors in effective treatment of TNBC. Activation of Wnt pathway was assessed in four TNBC cell lines (BT-549, MDA-MB-231, HCC-1143 and HCC-1937), and the ER+ cell line MCF-7 using confocal microscopy and Western blot analysis of pathway components. Effectiveness of five different Wnt pathway inhibitors (iCRT-3, iCRT-5, iCRT-14, IWP-4 and XAV-939) on cell

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR) Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD)

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR) Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD)

Breast cancer is one of the most common cancer deaths in female. Estrogen receptor(ER)-negative breast cancer constitutes approximately 30 % of breast cancer cases. Triple-negative is defined as a subgroup with ER, PR(progesterone receptor) and human epidermal growth factor receptor 2 (HER2) all negative. TNBC are assumed importance for its molecular characters, aggressive progress and distinct tranfer ability [1, 2]. Beneficial results of current anti-HER2 or hormonal therapy could not improve the curative effect of chemotherapy. In the absence of proper treatments, TNBC often progresses to metastatic lesions in the brain and lung in three years. Once being with metastasis, the 5-year survival rate of TNBC would be less than 30 %. Newly therapies are urgently needed to improve the prognosis for TNBC patients. Actually, TNBCs exhibit a high level of molecular heterogeneity without high-frequency driver mutations. About 60-70 % of TNBCs has mutations of p53. For PIK3CA mutations, it would be 11 ...

TY - JOUR. T1 - Estrogen receptor binding affinity and uterotrophic activity of triphenylhaloethylenes. AU - DeSombre, Eugene R.. AU - Mease, Ronnie C.. AU - Sanghavl, Jigi. AU - Singh, Tej. AU - Seevers, Robert H.. AU - Hughes, Alun. N1 - Funding Information: Acknowledgements-Wteh ank RestitutoD izon for his able supportin the animal studies,D r S. John Gatley for his analysiso f the metabolicp roductso f the diacetatesa, nd Johanna Darden for her help in preparationo f the manuscript. Supported by the NIH (CA27476, CA14599, HD15513), DOE Contract W-31-109-ENG-38a nd the Julius J. Reingold Fellowship Fund.. PY - 1988/6. Y1 - 1988/6. N2 - Radiohalogenated estrogens have considerable potential for estrogen receptor-directed imaging and therapy for cancers which contain such receptors. In an effort to evaluate the potential of the triphenyl ethylene structure for such purposes we have synthesized 3 series of 2-halosubstituted triphenylethylenes containing oxygen functions in the 4 position of both ...

[77 Pages Report] Check for Discount on Estrogen Receptor (ER Alpha or Estradiol Receptor or Nuclear Receptor Subfamily 3 Group A Member 1 or NR3A1 or ESR1) - Pipeline Review, H2 2017 report by Global Markets Direct. Estrogen Receptor (ER Alpha or Estradiol Receptor or Nuclear Receptor...

Objective To evaluate the frequency of the estrogen receptor (ER) gene PvuII and XbaI polymorphisms and their associations with bone mineral density (BMD) in a group of postmenopausal Turkish women. ...

Uncommon mutations in three genes in estrogen receptor positive breast cancer have a negative impact on disease prognosis reports a team of British and Australian researchers in |i||link https://www.nature.com/articles/s41467-018-05914-x|Nature Communications|/link|. |/i| |i||br /||/i|

Aromatase is one of the important target for drugs that interfere with production of estrogen in the treatment of estrogen receptor positive breast cancer. Therefore the discovery of novel aromatase inhibitors that can kill the growth of cancer cells selectively with minimal toxic effects on normal healthy cells is desirable. In the present study, novel 5-(4-bromophenyl)-1,3-oxazole derivatives were synthesized, characterized and screened for their biological effect. A series of novel 5-(4-bromophenyl)-1,3-oxazole derivatives OXZ-1 to 12 were docked by Auto Dock tool to evaluate their aromatase inhibition. All the derivatives were synthesized by using versatile and convenient route. Spectroscopic techniques have characterized the synthesized compounds in order to validate their structures. A total of 12 compounds were synthesized and evaluated for their in-vitro aromatase inhibitory activity and all derivatives were tested to assess their cytotoxic effect against breast cancer cell lines ...

This article reported on a rather large trial known as ATLAS that involved almost 7,000 women, from over 30 countries, with estrogen receptor positive breast cancer. They were randomized to tamoxifen for 10 years versus those who stopped after the traditional 5 year time period. The group who took tamoxifen for 10 years had less recurrence of their breast cancer even after they stopped tamoxifen at the 10 year time frame. In addition, there were fewer women who died in the group that took tamoxifen for 10 years versus those who took it for 5 years. There were slightly more cases of uterine cancer in the women who took tamoxifen for the extra 5 years. However, the number of deaths from this was much smaller than the incremental number of deaths from breast cancer.. ...

Estrogen receptor (ER) positive rates in breast cancer may be influenced by grade, stage, age and race. This study reviews the ER positive rates over a 15-year period at the University Malaya Medical Centre, Kuala Lumpur, Malaysia. Data on ER status of 3557 patients from 1994 to 2008 was analyzed. ER status was determined by immunohistochemistry with a cut-off point of 10%. ER positivity increased by about 2% for every 5-year cohort, from 54.5% in 1994-1998 to 58.4% in 2004-2008. Ethnicity and grade were significantly associated with ER positivity rates: Malay women were found to have a higher risk of ER negative tumors compared with Chinese women. Grade 1 cancers were nine times more likely to be ER positive compared with grade 3 cancers. In summary, the proportion of ER positive cancers increased with each time period, and ethnicity and grade were independent factors that influenced ER positive rates. ...

TY - JOUR. T1 - Estrogen receptor alpha signaling promotes Sle1-induced loss of tolerance and immune cell activation and is responsible for sex bias in B6.Sle1 congenic mice. AU - Yoachim, Shayla D. AU - Nuxoll, Jenny S.. AU - Bynoté, Kimberly K.. AU - Gould, Karen A. PY - 2015/6/1. Y1 - 2015/6/1. N2 - Sex bias in lupus incidence is thought to be due, in part, to the ability of estrogens to promote loss of tolerance. Previously, we showed that estrogens promote lupus via estrogen receptor α (ERα). C57BL/6 (B6) mice carrying the Sle1 lupus susceptibility locus (B6.Sle1) display loss of tolerance and develop anti-nuclear antibodies and immune cell hyperactivation. The incidence of loss of tolerance in B6.Sle1 females is greater than in males. Here, we show that a deficiency of either estrogens or ERα attenuates loss of tolerance and autoantibody development in B6.Sle1 females. Furthermore, we demonstrate that immune cell activation in B6.Sle1 mice shows sex bias and that ERα deficiency ...

Estrogen receptors (ERs) are steroid hormone receptors important in development, growth, and reproduction. The 2 well characterized ERs, alpha and beta, interact with a variety of receptor coregulators. These coregulators bind and direct the ERs to specific promoters, varying the ER target genes transcribed to modulate signaling responses. ERs play a large role in cancers of the female reproductive system, especially breast cancer. ER positive breast cancers can be treated with antiestrogen therapy, often yielding an improved prognosis. These types of treatments use selective estrogen receptor modulators to diminish side effects on other organs expressing estrogen receptors. In addition, estrogen signaling plays a role in other pathophysiological conditions such as osteoporosis and obesity. The mechanisms of estrogen receptor signaling are not entirely understood since there are many coregulators as well as a myriad of target genes ...

TY - JOUR. T1 - Prognostic Impact of HOTAIR Expression is Restricted to ER-Negative Breast Cancers. AU - Gökmen-Polar, Yesim. AU - Vladislav, I. Tudor. AU - Neelamraju, Yaseswini. AU - Janga, Sarath C.. AU - Badve, Sunil. PY - 2015. Y1 - 2015. N2 - Expression of HOX transcript antisense intergenic RNA (HOTAIR), a large intergenic noncoding RNA (lincRNA), has been described as a metastases-associated lincRNA in various cancers including breast, liver and colon cancer cancers. We sought to determine if expression of HOTAIR could be used as a surrogate for assessing nodal metastases and evaluated RNA in situ hybridization (RNA-ISH) assay in a tissue microarray constructed from 133 breast cancer patients. The prognostic value of HOTAIR was further validated in large cohorts using The Cancer Genome Atlas (TCGA) breast cancer subjects. RNA-ISH analysis was successful in 94 cases (17% cases scored 0, 32.9% scored 1, 30.8% scored 2, and 19.1% scored 3). The expression of HOTAIR did not correlate with ...

Background The aim of this retrospective study was to determine whether progesteron receptor (PgR) status have an influence on the prognosis of estrogen receptor positive (ER+)/HER2-negative breast carcinoma (BC).. Methods We retrospectively reviewed the medical files of 1680 operable BC patients (pts) diagnosed between 1996 and 2011 and 456 of whom ER,PgR and HER2 status known were included in this study. Patients were categorized into 2 groups; as group A (ER + /PgR-/HER2-negative) and group B (ER + /PgR + /HER2-negative). Twenty one percent (97 pts) of the pts were in group A.. Results Median follow up was 33.5 (0-177) months. Median age was 54 (21-90) years. Sixty-one percent (278) of the pts had node-positive BC. Sixty percent (276) of the pts were postmenopausal. Eighty percent (365) of the pts received adjuvant chemotherapy (ACT). Adjuvant hormonotherapy (AHT) was recommended to nearly all patients (mostly tamoxifen). Pts in group A had significantly higher lymph node positive disease as ...

The majority of breast cancers are also sensitive to estrogen, meaning that estrogen promotes tumor growth.. These cancers are called hormone receptor positive breast cancers.. For people with these cancers, treatments to lower estrogen levels or block estrogen production can be used to help prevent cancer recurrence after surgery, or to slow cancer growth.. According to Breast Cancer.org, alcohol can increase a womans risk of hormone-receptor-positive breast cancer.. Alcohol also enhances the effects of estrogen in driving the growth of breast cancer cells, according to 2016 research at the University of Houston.. Endometriosis is another estrogen-dependent disease.. Reducing estrogen levels and providing non-estrogen treatments have all been considered for the treatment of endometriosis.. The problem is that reducing the levels of estrogen in women can lead to infertility.. A study by the Womens Health Initiative showed that BY REDUCING HORMONES -. ( SPECIFICALLY ESTROGEN )- had significant ...

The majority of breast cancers are also sensitive to estrogen, meaning that estrogen promotes tumor growth.. These cancers are called hormone receptor positive breast cancers.. For people with these cancers, treatments to lower estrogen levels or block estrogen production can be used to help prevent cancer recurrence after surgery, or to slow cancer growth.. According to Breast Cancer.org, alcohol can increase a womans risk of hormone-receptor-positive breast cancer.. Alcohol also enhances the effects of estrogen in driving the growth of breast cancer cells, according to 2016 research at the University of Houston.. Endometriosis is another estrogen-dependent disease.. Reducing estrogen levels and providing non-estrogen treatments have all been considered for the treatment of endometriosis.. The problem is that reducing the levels of estrogen in women can lead to infertility.. A study by the Womens Health Initiative showed that BY REDUCING HORMONES -. ( SPECIFICALLY ESTROGEN )- had significant ...

From: NAME: Les Davies FUNC: Therapeutic Goods Admin TEL: (06)289 7182 - MDP 88 ,DAVIES LES at A1@CBR, To: mx%bioforum at net.bio.net@cnb09w at mrgate@cbr Message-id: D752IOD2V16Y From: NAME: Les Davies FUNC: Therapeutic Goods Admin TEL: (06)289 7182 - MDP 88 ,DAVIES LES at A1@CBR, Subject: (1) Estrogen receptor assays & (2) the nervous system Date: 04-Nov-1996 Posted-date: 04-Nov-1996 Precedence: 1 To: mx5biosci-request at net.bio.net@cnb09w at mrgate@cbr (1) Estrogen receptor assays Noted a reply to Raymond Pierre (from JS Amenta?) about receptor binding assays for estrogen receptors - the comment that the point is to inhibit non-specific binding and not affect the specific receptor binding is not really correct - non-specific binding is not inhibitable. In receptor binding assays, an excess of a known receptor binding compound is added (to a separate set of assay tubes from the control binding tubes) to make sure that specific receptors are fully saturated and then no tritiated label ...

The healthy breast is a tissue composed of centrally located milk producing glands connected to the nipple by ducts, surrounded by fat tissue and connective tissue. The growth of the breast is primarily mediated by the estrogens, while the androgens mediate tissue homeostasis and protect against growth signals. In breast cancer, the cells of the glands or ducts undergo malignant transformation, and start proliferating in an uncontrollable fashion. Breast cancer is the most common malignancy in women, and it is estimated that 10% of all women will be diagnosed with breast cancer during their life-time. The primary classification of breast cancer is based mainly on the expression of the estrogen receptor, and 70-80% of breast cancers are estrogen receptor positive, and are classified as luminal. The remaining breast cancers are classified into HER2 positive or triple negative breast cancer. Out of all breast cancers, ~80% are androgen receptor positive. This varies in different subtypes, however, ...

TY - JOUR. T1 - Alfa and beta estrogen receptors and the biliary tree. AU - Alvaro, Domenico. AU - Alpini, G.. AU - Onori, P.. AU - Franchitto, A.. AU - Glaser, S. S.. AU - Le Sage, G.. AU - Folli, F.. AU - Attili, A. F.. AU - Gaudio, E.. N1 - Funding Information: Supported by the grant MURST 2000 (40% funds) # MM06215421/2 and by an NIH grant DK58411 and by VA Merit Award to Dr. G. Alpini.. PY - 2002/7/31. Y1 - 2002/7/31. N2 - This manuscript summarizes recent data showing that estrogens and their receptors play an important role in modulating cholangiocyte proliferation. We have recently demonstrated that rat cholangiocytes express both estrogen receptors (ER)-α and -β subtypes, while hepatocytes only express ER-α. ER and especially the ER-β subtype, are overexpressed in cholangiocytes proliferating after bile duct ligation (BDL) in the rat, in association with enlarged bile duct mass and with enhanced estradiol serum levels. Cholangiocyte proliferation, during BDL, is impaired by estrogen ...

TY - JOUR. T1 - A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance. AU - Miller, Todd W.. AU - Balko, Justin M.. AU - Ghazoui, Zara. AU - Dunbier, Anita. AU - Anderson, Helen. AU - Dowsett, Mitch. AU - González-Angulo, Ana M.. AU - Mills, Gordon B.. AU - Miller, William R.. AU - Wu, Huiyun. AU - Shyr, Yu. AU - Arteaga, Carlos L.. PY - 2011/4/1. Y1 - 2011/4/1. N2 - Purpose: Although most patients with estrogen receptor α (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped. Experimental Design: We adapted four ER+ human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression profiles of long-term estrogen-deprived (LTED) cells to ...

Inclusion Criteria:. - 1 18 and 75 years old; ECOG physical condition: 0 - 1 points; expected survival time more than 3 months》 2 Histological or cytological diagnosis of relapsed/metastatic triple receptor negative breast cancer (TNBC).TNBC is defined negatively expression of estrogen(ER), progesterone(PR) and human epidermal receptor-2(HER2).If there is a pathology report of the metastasis, take the histopathology of the metastases as standard. Negative of ER and PR is defined as expression of ER,PR,1% of the tumor cells by immunohistochemistry (IHC). HER2-negative is defined as a score of 0 and 1+ by IHC, or IHC 2+ & fluorescent in situ hybridization (FISH)negative. If the ER2 test result is 0 or 1+ by IHC, FISH detection is optional, but the result must be negative.. 3 Patients had at least one measurable lesion (RECIST 1.1); 4 Participants has received prior anthracyclines and/or taxanes in first-line therapy. Disease progressed after latest chemotherapy. For adjuvant therapy/neoadjuvant ...

Recently in the pig hypothalamus a vasopressin- and oxytocin-containing nucleus was identified which, like the supraoptic nucleus, becomes sexually dimorphic after puberty. Following the increase in circulating steroids at puberty, the vasopressin- and oxytocin-containing nucleus becomes twice as large in both males and females. In adulthood, the vasopressin- and oxytocin-containing nucleus of females is approximately twice as large as that in males. Because these alterations are possibly due to an influence of gonadal steroids, i.e. estrogens, the vasopressin- and oxytocin-containing the presence of estrogen receptors. In addition to the area of the vasopressin- and oxytocin-containing nucleus, the present study documented the distribution of estrogen receptors in the septal area and other parts of the hypothalamus of intact post-pubertal male and female pigs, by utilizing immunocytochemical methodology. Intense nuclear estrogen receptor staining was found in a number of areas, i.e. the medial preoptic

TY - JOUR. T1 - Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors. AU - Droog, Marjolein. AU - Nevedomskaya, Ekaterina. AU - Dackus, Gwen M.. AU - Fles, Renske. AU - Kim, Yongsoo. AU - Hollema, Harry. AU - Mourits, Marian. AU - Nederlof, Petra M.. AU - Van Boven, Hester H.. AU - Linn, Sabine C.. AU - Van Leeuwen, Flora E.. AU - Wessels, Lodewyk F.A.. AU - Zwart, Wilbert. PY - 2017/2/21. Y1 - 2017/2/21. N2 - The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial ...

Receptors are proteins on cells that may attach to hormones that circulate in the blood. Normal breast cells and some breast cancer cells have receptors that attach to estrogen and progesterone. These two hormones often fuel the growth of breast cancer cells.. A biopsy can check to see if the cells have estrogen or progesterone receptors.. Cancer cells may contain neither, one, or both of these receptors. Breast cancers that contain estrogen receptors are called ER-positive (ER+) cancers, while those containing progesterone receptors are called PR-positive (PR+) cancers.. Women with hormone receptor-positive cancers tend to have a better prognosis and are much more likely to respond to hormone therapy than women with cancers without these receptors.. The ACS says that about one of five breast cancers have too much of a growth-promoting protein called HER2. The HER2 gene instructs the cells to make this protein. Tumors with increased levels of HER2 are referred to as HER2-positive.. Because ...

Breast cancer is a major cause of death worldwide. Human cytochrome P450 (CYP) 1B1 is a key enzyme in the metabolism of 17β-estradiol, and CYP1B1-metabolized 4-hydroxyestradiol is a marker for breast cancer. Furthermore, overexpression of cyclooxygenase-2 (COX-2), which produces prostaglandin E2 (PGE2), has been detected in invasive breast carcinomas. However, the interaction between PGE2 and CYP1B1 expression in human breast cancer is unclear. Here, we investigated the effect of PGE2 on CYP1B1 expression and its mechanism in breast cancer cells. PGE2 significantly increased CYP1B1 protein and messenger RNA expression and dose dependently enhanced CYP1B1 promoter activity in human breast cancer MCF-7 cells. Transient transfection with human CYP1B1 (hCYP1B1) deletion promoter constructs and cotreatment with inhibitors revealed that the estrogen response element contributed to the effects of PGE2. CYP1B1 expression was not affected by PGE2 in estrogen receptor (ER) α-negative MDA-MB-231 breast ...

Oncogenesis in breast cancer is often associated with excess estrogen receptor α(ERα) activation and overexpression of its coactivators. LRP16 is both an ERα target gene and an ERα coactivator, and plays a crucial role in ERα activation and proliferation of MCF-7 breast cancer cells. However, the regulation of the functional availability of this coactivator protein is not yet clear. Yeast two-hybrid screening, GST pulldown and coimmunoprecipitation (CoIP) identified the cytoplasmic intermediate filament protein keratin 18 (K18) as a novel LRP16-interacting protein. Fluorescence analysis revealed that GFP-tagged LRP16 was primarily localized in the nuclei of mock-transfected MCF-7 cells but was predominantly present in the cytoplasm of K18-transfected cells. Immunoblotting analysis demonstrated that the amount of cytoplasmic LRP16 was markedly increased in cells overexpressing K18 whereas nuclear levels were depressed. Conversely, knockdown of endogenous K18 expression in MCF-7 cells significantly

The amounts of estrogen receptor (ER) and progesterone receptor (PgR) in a primary tumor are predictive of the response to endocrine therapies of breast cancer. Several patients with ER-positive primary tumors relapse after adjuvant endocrine therapy with no ER expression in the recurrent tissue; much fewer with a recurrent disease after an ER-negative primary tumor may become endocrine responsive. These sequences of events indicate that a phenotype based on ER expression may not be a permanent feature of breast cancer. Ten patients with advanced breast cancer whose tumors overexpressed HER-2, but not ER or PgR, were treated with weekly trastuzumab at standard doses with or without chemotherapy. Three out of 10 patients showed overexpression of ERs first appearing after 9, 12 and 37 weeks, respectively, from the initiation of trastuzumab. Two of these patients were subsequently treated with endocrine therapy alone: one of them received letrozole for 3 years without evidence of progression. Therapeutic

The cytotoxic activity of PINO on human breast tumour cells is a debated issue. Previously, Chin et al. [25] described that PINO has a cytotoxic effect against MCF7 breast cancer cells (ED50 = 4.74 μM); however, in a later article [21], the same author found no cytotoxic effects. Surprisingly, the range of concentrations used in both studies was not specified. In addition, the cytotoxic effects of PINO in MDA-MB-231 cells have not been previously reported. In contrast, we tested a wide range of PINO concentrations and showed that there was cytotoxic activity at different concentrations in both human breast tumour cells tested. While PINO showed cytotoxic activity in both types of human breast tumour cells tested, the effect was more pronounced in negative oestrogen receptor tumour cells compared to oestrogen receptor-positive tumour cells (Figs. 4 and 5). In addition, for the first time, we describe the effects of PINO on human mammary epithelial cells. Our results suggest that PINO ranging ...