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Sample records for receptor er positive

  1. Activated HER-receptors in predicting outcome of ER-positive breast cancer patients treated with adjuvant endocrine therapy

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    Larsen, Mathilde Skaarup; Bjerre, Karsten; Lykkesfeldt, Anne Elisabeth

    2012-01-01

    The four human epidermal growth factor receptors (HER1-4) are involved in growth stimulation and may play a role in endocrine resistance. The receptors form dimers, leading to activation by mutual phosphorylation. Our purpose was to explore the role of the activated receptors (pHER1, pHER2, pHER3......) in endocrine treated breast cancer in terms of co-expression and association with disease-free survival (DFS) in 1062 patients with ER-positive tumors. Furthermore, HER2 amplification was evaluated. We found positive associations between the phosphorylated receptors. pHER1 and pHER3 were co-expressed with one...

  2. Identification of Potential Glycoprotein Biomarkers in Estrogen Receptor Positive (ER+ and Negative (ER- Human Breast Cancer Tissues by LC-LTQ/FT-ICR Mass Spectrometry

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    Suzan M. Semaan, Xu Wang, Alan G. Marshall, Qing-Xiang Amy Sang

    2012-01-01

    Full Text Available Breast cancer is the second most fatal cancer in American women. To increase the life expectancy of patients with breast cancer new diagnostic and prognostic biomarkers and drug targets must be identified. A change in the glycosylation on a glycoprotein often causes a change in the function of that glycoprotein; such a phenomenon is correlated with cancerous transformation. Thus, glycoproteins in human breast cancer estrogen receptor positive (ER+ tissues and those in the more advanced stage of breast cancer, estrogen receptor negative (ER- tissues, were compared. Glycoproteins showing differences in glycosylation were examined by 2-dimensional gel electrophoresis with double staining (glyco- and total protein staining and identified by reversed-phase nano-liquid chromatography coupled with a hybrid linear quadrupole ion trap/ Fourier transform ion cyclotron resonance mass spectrometer. Among the identified glycosylated proteins are alpha 1 acid glycoprotein, alpha-1-antitrypsin, calmodulin, and superoxide dismutase mitochondrial precursor that were further verified by Western blotting for both ER+ and ER- human breast tissues. Results show the presence of a possible glycosylation difference in alpha-1-antitrypsin, a potential tumor-derived biomarker for breast cancer progression, which was expressed highest in the ER- samples.

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

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    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.

  4. Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen.

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    Snell, Cameron E; Gough, Madeline; Middleton, Kathryn; Hsieh, Michael; Furnas, Lauren; Seidl, Brenton; Gibbons, Kristen; Pyke, Christopher; Shannon, Catherine; Woodward, Natasha; Armes, Jane E

    2017-11-01

    Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (-) breast cancer could provide more accurate prognostic information. The retrospective cohort included 229 patients from a single institution with ER+, HER2- breast cancer who had synchronous ALN metastatic disease (2005-2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. One patient had an ER+ primary tumour, which was ER- in the ALN metastasis. 27 (11.3%) were PR- in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR- in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR- metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR- metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  5. A Phase II Study Evaluating the Role of Androgen Receptors as Targets for Therapy of Pre-treated Post-menopausal Patients With ER/PgR-negative/AR-positive or ER and/or PgRpositive/ AR-positive Metastatic Breast Cancer (ARTT)

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    2016-09-28

    Metastatic Breastcancer; Estrogen Receptor Positive Breast Cancer; Estrogen Receptor Negative Neoplasm; Progesterone Receptor Positive Tumor; Progesterone Receptor Negative Neoplasm; Androgen Receptor Gene Overexpression

  6. Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines.

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    Kui Shen

    Full Text Available Breast cancer patients have different responses to chemotherapeutic treatments. Genes associated with drug response can provide insight to understand the mechanisms of drug resistance, identify promising therapeutic opportunities, and facilitate personalized treatment. Estrogen receptor (ER positive and ER negative breast cancer have distinct clinical behavior and molecular properties. However, to date, few studies have rigorously assessed drug response genes in them. In this study, our goal was to systematically identify genes associated with multidrug response in ER positive and ER negative breast cancer cell lines. We tested 27 human breast cell lines for response to seven chemotherapeutic agents (cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, and paclitaxel. We integrated publicly available gene expression profiles of these cell lines with their in vitro drug response patterns, then applied meta-analysis to identify genes related to multidrug response in ER positive and ER negative cells separately. One hundred eighty-eight genes were identified as related to multidrug response in ER positive and 32 genes in ER negative breast cell lines. Of these, only three genes (DBI, TOP2A, and PMVK were common to both cell types. TOP2A was positively associated with drug response, and DBI was negatively associated with drug response. Interestingly, PMVK was positively associated with drug response in ER positive cells and negatively in ER negative cells. Functional analysis showed that while cell cycle affects drug response in both ER positive and negative cells, most biological processes that are involved in drug response are distinct. A number of signaling pathways that are uniquely enriched in ER positive cells have complex cross talk with ER signaling, while in ER negative cells, enriched pathways are related to metabolic functions. Taken together, our analysis indicates that distinct mechanisms are involved in

  7. Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive Breast Cancer.

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    Chimge, Nyam-Osor; Ahmed-Alnassar, Sara; Frenkel, Baruch

    2017-02-16

    RUNX1 plays opposing roles in breast cancer: a tumor suppressor in estrogen receptor-positive (ER+) disease and an oncogenic role in ER-negative (ER-) tumors. Potentially mediating the former, we have recently reported that RUNX1 prevents estrogen-driven suppression of the mRNA encoding the tumor suppressor AXIN1. Accordingly, AXIN1 protein expression was diminished upon RUNX1 silencing in ER+ breast cancer cells and was positively correlated with AXIN1 protein expression across tumors with high levels of ER. Here we report the surprising observation that RUNX1 and AXIN1 proteins are strongly correlated in ER- tumors as well. However, this correlation is not attributable to regulation of AXIN1 by RUNX1 or vice versa. The unexpected correlation between RUNX1, playing an oncogenic role in ER- breast cancer, and AXIN1, a well-established tumor suppressor hub, may be related to a high ratio between the expression of variant 2 and variant 1 (v2/v1) of AXIN1 in ER- compared with ER+ breast cancer. Although both isoforms are similarly regulated by RUNX1 in estrogen-stimulated ER+ breast cancer cells, the higher v2/v1 ratio in ER- disease is expected to weaken the tumor suppressor activity of AXIN1 in these tumors.

  8. Targeted Radiotherapy of Estrogen Receptor Positive Tumors

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    Raghavan Rajagopalan

    2006-08-31

    The overall objectives of the proposal were to develop estrogen receptor (ER) binding small molecule radiopharmaceuticals for targeted radiotherapy of ER positive (ER+) tumors. In particular, this proposal focused on embedding a {sup 186,188}Re or a {sup 32}P radionuclide into an estrogen steroidal framework by isosteric substitution such that the resulting structure is topologically similar to the estrogen (estrogen mimic). The estrogen mimic molecules expected to bind to the ER and exhibit biodistribution akin to that of native estrogen due to structural mimicry. It is anticipated that the {sup 186,188}Re- or a {sup 32}P-containing estrogen mimics will be useful for targeted molecular radiotherapy of ER+ tumors. It is well established that the in vivo target tissue uptake of estrogen like steroidal molecules is related to the binding of the steroids to sex hormone binding globulin (SHBG). SHBG is important in the uptake of estrogens and testosterone in target tissues by SHBG receptors on the cell surface. However, hitherto the design of estrogen like small molecule radiopharmaceuticals was focused on optimizing ER binding characteristics without emphasis on SHBG binding properties. Consequently, even the molecules with good ER affinity in vitro, performed poorly in biodistribution studies. Based on molecular modeling studies the proposal focused on developing estrogen mimics 1-3 which were topologically similar to native estrogens, and form hydrogen bonds in ER and SHBG in the same manner as those of native estrogens. To this end the technical objectives of the proposal focused on synthesizing the rhenium-estrone and estradiol mimics 1 and 2 respectively, and phosphorous estradiol mimic 3 and to assess their stability and in vitro binding characteristics to ER and SHBG.

  9. Pancreatic insulin content regulation by the estrogen receptor ER alpha.

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    Paloma Alonso-Magdalena

    Full Text Available The function of pancreatic beta-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ER alpha and ER beta, are important molecules involved in glucose metabolism, yet their role in pancreatic beta-cell physiology is still greatly unknown. In this report we show that both ER alpha and ER beta are present in pancreatic beta-cells. Long term exposure to physiological concentrations of 17beta-estradiol (E2 increased beta-cell insulin content, insulin gene expression and insulin release, yet pancreatic beta-cell mass was unaltered. The up-regulation of pancreatic beta-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA. The use of ER alpha and ER beta agonists as well as ER alphaKO and ER betaKO mice suggests that the estrogen receptor involved is ER alpha. The up-regulation of pancreatic insulin content by ER alpha activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.

  10. Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers.

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    Flågeng, Marianne Hauglid; Larionov, Alexey; Geisler, Jürgen; Knappskog, Stian; Prestvik, Wenche S; Bjørkøy, Geir; Lilleng, Peer Kåre; Dixon, J Michael; Miller, William R; Lønning, Per Eystein; Mellgren, Gunnar

    2017-01-01

    While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. 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.......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...

  12. Study of Estrogen Receptor and Progesterone Receptor Expression in Breast Ductal Carcinoma In Situ by Immunohistochemical Staining in ER/PgR-Negative Invasive Breast Cancer.

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    Dobrescu, Andrei; Chang, Monique; Kirtani, Vatsala; Turi, George K; Hennawy, Randa; Hindenburg, Alexander A

    2011-01-01

    Background. To our knowledge, the hormone receptor status of noncontiguous ductal carcinoma in situ (DCIS) occurring concurrently in ER/PgR-negative invasive cancer has not been studied. The current study was undertaken to investigate the ER/PgR receptor status of DCIS of the breast in patients with ER/PgR-negative invasive breast cancer. Methods. We reviewed the immunohistochemical (IHC) staining for ER and PgR of 187 consecutive cases of ER/PgR-negative invasive breast cancers, collected from 1995 to 2002. To meet the criteria for the study, we evaluated ER/PgR expression of DCIS cancer outside of the invasive breast cancer. Results. A total of 37 cases of DCIS meeting the above criteria were identified. Of these, 16 cases (43.2%) showed positive staining for ER, PgR, or both. Conclusions. In our study of ER/PgR-negative invasive breast cancer we found that in 8% of cases noncontiguous ER/PR-positive DCIS was present. In light of this finding, it may be important for pathologists to evaluate the ER/PgR status of DCIS occurring in the presence of ER/PgR-negative invasive cancer, as this subgroup could be considered for chemoprevention.

  13. Differentiated expression of estrogen receptors (ER and progesterone receptors (PgR in ductal breast cancers.

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    Piotr Dziegiel

    2009-05-01

    Full Text Available Contents of estrogen receptors (ER and progesterone receptors (PgR in cells of breast cancers represent strong predictive factors. The higher is the contents of ER and PgR in breast cancer, the higher is a probability of obtaining a response to hormonal therapy and prognosis for the patient is better. In a routine manner, all tumours of mammary gland are subjected to evaluation of ER and PgR expression using immunohistochemistry. Forty ductal breast cancers (pT2N0 were subjected to an immunohistochemical evaluation (IHC aimed at detection of ER and PgR expression. From every tumour three samples were taken for immunohistochemical studies: the lateral one from the side of axilla (ER-1; PgR-1; the median one (ER-2; PgR-2 and the medial one from the side of sternum (ER-3; PgR-3. The levels of both ER and PgR expression proved to be highly differentiated between the medial zone of the tumour and its periphery. The distinct expression of ER and PgR in ductal breast cancers, dependent on evaluated zone of the tumour, confirms its heterogeneous character and exerts an effect on the type of applied treatment.

  14. Reelin and its receptors, VLDLR and ApoER2, in melanocytic nevi.

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    Mihail, A; Coman, G; Staniceanu, F; Coman, L; Zurac, S; Coman, O A

    2017-01-01

    Reelin is an extracellular signaling protein synthesized by Cajal-Retius cells in utero and early after birth, its presence being signaled in adult life too. Reelin acts on its receptors, VLDLR and ApoER2, acting on cytoskeleton, controlling migration and subsequently positioning and stabilizing the cortical neurons. We investigated the reelin presence and its receptors, VLDLR and ApoER2, in melanocytic nevi considering the neural crest origin of the nevus cells and their migration into skin during embrionary period. Melanocytic nevi present a strict cellular architecture and an increased malignant transforming capacity. We investigated reelin presence in 32 melanocytic nevi (5 junctional, 27 compound or 14 dysplastic nevi and 18 non dysplastic nevi). The assessment of reelin presence was performed by histological semiquantitative criteria. Results showed the presence of reelin in 29 cases (29/ 32). The presence of reelin was elevated in junctional areas as in dysplastic nevi. VLDLR presented positive values in 16 cases (16/ 32) and ApoER2 was weak positive in 7 cases. Reelin or its receptors was peritumorally absent. Our study showed the presence of reelin in nevus cells from cutaneous melanocytic nevi and, in these cells, only the VLDLR receptor was present in half of the cases. The significance of the reelin presence in cutaneous nevus cells may be hypothetically considered correlated with the position maintenance of the nevus cells or migration of these cells in malignant transforming situation. Abbreviations: ApoER2 = apolipoprotein receptor 2, VLDLR = very low density lipoprotein receptor, DAB-1 = DIABLO protein, HMB45 = gene HMB45.

  15. Survival is associated with complete response on MRI after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer

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    Loo, Claudette E; Rigter, Lisanne S; Pengel, Kenneth E; Wesseling, Jelle; Rodenhuis, Sjoerd; Peeters, Marie-Jeanne T F D Vrancken; Sikorska, Karolina; Gilhuijs, Kenneth G A|info:eu-repo/dai/nl/143937979

    2016-01-01

    BACKGROUND: Pathological complete remission (pCR) of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We

  16. Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.

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    Arpino, Grazia; Weiss, Heidi; Lee, Adrian V; Schiff, Rachel; De Placido, Sabino; Osborne, C Kent; Elledge, Richard M

    2005-09-07

    Clinical data indicate that estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) breast cancers are less sensitive to tamoxifen than are ER+/PR+ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER+/PR- breast tumors are more likely than ER+/PR+ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy. Clinical and biological features of 31 415 patients with ER+/PR+ tumors were compared with those of 13,404 patients with ER+/PR- tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11,399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan-Meier analyses, and all statistical tests were two-sided. ER+/PR- tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER+/PR+ tumors. Furthermore, three times as many ER+/PR- tumors as ER+/PR+ tumors expressed HER-1 (25% versus 8%; P HER-1-expressing tumors than with HER-1-negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER+/PR+ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER+/PR- tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence. ER+/PR- tumors express higher levels of HER-1 and HER-2 and

  17. ER-mediated control for abundance, quality, and signaling of transmembrane immune receptors in plants

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    Nico eTintor

    2014-02-01

    Full Text Available Plants recognize a wide range of microbes with cell-surface and intracellular immune receptors. Transmembrane pattern recognition receptors (PRRs initiate immune responses upon recognition of cognate ligands characteristic of microbes or aberrant cellular states, designated microbe-associated molecular patterns (MAMPs or danger-associated molecular patterns (DAMPs, respectively. Pattern-triggered immunity (PTI provides a first line of defense that restricts the invasion and propagation of both adapted and non-adapted pathogens. Receptor kinases (RKs and receptor-like proteins (RLPs with an extracellular leucine-rich repeat (LRR or lysine-motif (LysM domain are extensively used as PRRs. The correct folding of the extracellular domain of these receptors is under quality control (QC in the endoplasmic reticulum (ER, which thus provides a critical step in plant immunity. Genetic and structural insight suggests that ERQC regulates not only the abundance and quality of transmembrane receptors but also affects signal sorting between multi-branched pathways downstream of the receptor. However, ERQC dysfunction can also positively stimulate plant immunity, possibly through cell death and DAMP signaling pathways.

  18. Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival.

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    Mori, Tomohisa; Hayashi, Teruo; Hayashi, Eri; Su, Tsung-Ping

    2013-01-01

    The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.

  19. Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers

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    Raj, Ganesh V; Sareddy, Gangadhara Reddy; Ma, Shihong; Lee, Tae-Kyung; Viswanadhapalli, Suryavathi; Li, Rui; Liu, Xihui; Murakami, Shino; Chen, Chien-Cheng; Lee, Wan-Ru; Mann, Monica; Krishnan, Samaya Rajeshwari; Manandhar, Bikash; Gonugunta, Vijay K; Strand, Douglas; Tekmal, Rajeshwar Rao; Ahn, Jung-Mo; Vadlamudi, Ratna K

    2017-01-01

    The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers. DOI: http://dx.doi.org/10.7554/eLife.26857.001 PMID:28786813

  20. Potential mechanisms underlying estrogen-induced expression of the molluscan estrogen receptor (ER) gene

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    Tran, Thi Kim Anh [School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308 (Australia); Department of Agriculture, Forestry and Fisheries, Vinh University, 182 Le Duan St., Vinh City, Nghe An (Viet Nam); MacFarlane, Geoff R. [School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308 (Australia); Kong, Richard Yuen Chong [Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong Special Administrative Region (China); O’Connor, Wayne A. [New South Wales Department of Primary Industries, Port Stephens Fisheries Institute, Taylors Beach, NSW 2316 (Australia); Yu, Richard Man Kit, E-mail: Richard.Yu@newcastle.edu.au [School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308 (Australia)

    2016-10-15

    Highlights: • This is the first report on the putative promoter sequence of a molluscan ER gene. • The gene promoter contains putative binding sites for direct and indirect interaction with ER. • E2 upregulates ER gene expression in the ovary in vitro and in vivo. • E2-induced gene expression may require a novel ligand-dependent receptor. • The ER proximal promoter is hypomethylated regardless of gene expression levels. - Abstract: In vertebrates, estrogens and estrogen mimicking chemicals modulate gene expression mainly through a genomic pathway mediated by the estrogen receptors (ERs). Although the existence of an ER orthologue in the mollusc genome has been known for some time, its role in estrogen signalling has yet to be deciphered. This is largely due to its constitutive (ligand-independent) activation and a limited mechanistic understanding of its regulation. To fill this knowledge gap, we cloned and characterised an ER cDNA (sgER) and the 5′-flanking region of the gene from the Sydney rock oyster Saccostrea glomerata. The sgER cDNA is predicted to encode a 477-amino acid protein that contains a DNA-binding domain (DBD) and a ligand-binding domain (LBD) typically conserved among both vertebrate and invertebrate ERs. A comparison of the sgER LBD sequence with those of other ligand-dependent ERs revealed that the sgER LBD is variable at several conserved residues known to be critical for ligand binding and receptor activation. Ligand binding assays using fluorescent-labelled E2 and purified sgER protein confirmed that sgER is devoid of estrogen binding. In silico analysis of the sgER 5′-flanking sequence indicated the presence of three putative estrogen responsive element (ERE) half-sites and several putative sites for ER-interacting transcription factors, suggesting that the sgER promoter may be autoregulated by its own gene product. sgER mRNA is ubiquitously expressed in adult oyster tissues, with the highest expression found in the ovary

  1. Rainbow trout estrogen receptor (ER) competitive bindng and vitellogenin induction agonism/antagonism data for 94 chemicals

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    U.S. Environmental Protection Agency — This dataset is from screening 94 diverse chemicals for estrogen receptor (ER) activation in a competitive rainbow trout ER binding assay and a trout liver slice...

  2. Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC).

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    Arnedos, M; Nerurkar, A; Osin, P; A'Hern, R; Smith, I E; Dowsett, M

    2009-12-01

    Analysis of estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC) is increasingly being conducted in core needle biopsies (CNBs) taken at diagnosis but the concordance with the excisional biopsy (EB) is poorly documented. Patients with EBC presenting to The Royal Marsden Hospital from June 2005 to September 2007 who had CNB and subsequent EB were included. ER and PgR were determined by immunohistochemistry (IHC) and graded from 0 to 8 (Allred score). HER2 was determined by IHC and scored from 0 to 3+. FISH analysis was carried out in HER2 2+ cases and in discordant cases. In all, 336 pairs of samples were compared. ER was positive in 253 CNBs (75%) for 255 EBs (76%) and was discordant in six patients (1.8%). PgR was positive in 221 CNBs (66%) and 227 (67.6%) EBs being discordant in 52 cases (15%). HER2 was positive in 41 (12.4%) of the 331 CNBs in which it was determined compared with 44 (13.3%) EBs and discordant in four cases (1.2%). CNB can be used with confidence for ER and HER2 determination. For PgR, due to a substantial discordance between CNB and EB, results from CNB should be used with caution.

  3. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor positive breast cancer

    Science.gov (United States)

    Meric-Bernstam, Funda; Gonzalez-Angulo, Ana Maria; Ferrer-Lozano, Jaime; Perez-Fidalgo, Jose A.; Cristofanilli, Massimo; Gómez, Henry; Arteaga, Carlos L.; Giltnane, Jennifer; Balko, Justin M.; Cronin, Maureen T; Jarosz, Mirna; Sun, James; Hawryluk, Matthew; Lipson, Doron; Otto, Geoff; Ross, Jeffrey S; Dvir, Addie; Soussan-Gutman, Lior; Wolf, Ido; Rubinek, Tamar; Gilmore, Lauren; Schnitt, Stuart; Come, Steven E.; Pusztai, Lajos; Stephens, Philip; Brown, Myles; Miller, Vincent A.

    2014-01-01

    Purpose We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone dependent breast cancer and to delineate the functional roles of the most commonly detected alterations. Experimental Design We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER positive (ER+/HER2–) and, as controls, 115 ER negative (ER−) tumors. The ER+ samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes. Results Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER+ metastatic disease. Overall, the frequency of these mutations was 12% (9/76, 95% CI 6%-21%) in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25, 95% CI 7%-41%). These mutations were not detected in primary or treatment naïve ER+ cancer or in any stage of ER− disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments. Conclusions In this study we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER positive breast cancer. PMID:24398047

  4. FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

    Science.gov (United States)

    Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel; Hollingsworth, Emporia F.; Creighton, Chad J.; Li, Fugen; Shea, Martin; Nardone, Agostina; De Angelis, Carmine; Heiser, Laura M.; Anur, Pavana; Wang, Nicholas; Grasso, Catherine S.; Spellman, Paul T.; Tsimelzon, Anna; Gutierrez, Carolina; Huang, Shixia; Edwards, Dean P.; Trivedi, Meghana V.; Rimawi, Mothaffar F.; Lopez-Terrada, Dolores; Hilsenbeck, Susan G.; Gray, Joe W.; Brown, Myles; Osborne, C. Kent; Schiff, Rachel

    2016-01-01

    Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors. PMID:27791031

  5. Role of dietary bioactive natural products in estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Bak, Min Ji; Das Gupta, Soumyasri; Wahler, Joseph; Suh, Nanjoo

    2016-10-01

    Estrogen receptor (ER)-positive breast cancer, including luminal-A and -B, is the most common type of breast cancer. Extended exposure to estrogen is associated with an increased risk of breast cancer. Both ER-dependent and ER-independent mechanisms have been implicated in estrogen-mediated carcinogenesis. The ER-dependent pathway involves cell growth and proliferation triggered by the binding of estrogen to the ER. The ER-independent mechanisms depend on the metabolism of estrogen to generate genotoxic metabolites, free radicals and reactive oxygen species to induce breast cancer. A better understanding of the mechanisms that drive ER-positive breast cancer will help optimize targeted approaches to prevent or treat breast cancer. A growing emphasis is being placed on alternative medicine and dietary approaches toward the prevention and treatment of breast cancer. Many natural products and bioactive compounds found in foods have been shown to inhibit breast carcinogenesis via inhibition of estrogen induced oxidative stress as well as ER signaling. This review summarizes the role of bioactive natural products that are involved in the prevention and treatment of estrogen-related and ER-positive breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Kinome wide functional screen identifies role of Polo-like kinase 1 (PLK1) in hormone-independent, ER-positive breast cancer

    Science.gov (United States)

    Bhola, Neil; Jansen, Valerie M.; Bafna, Sangeeta; Giltnane, Jennifer M.; Balko, Justin M.; Estrada, Mónica V.; Meszoely, Ingrid; Mayer, Ingrid; Abramson, Vandana; Ye, Fei; Sanders, Melinda; Dugger, Teresa C.; Van Allen, Eliezer; Arteaga, Carlos L.

    2014-01-01

    Estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens but eventually become estrogen-independent and recur. ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki67 score in primary ER+ breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacological inhibition of PLK1 with volasertib, a small molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared to parental MCF7 cells. Further, JUNB and BCL2L1 (which encodes anti-apoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER+ human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy. PMID:25480943

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Risk Factors That Increase Risk of Estrogen Receptor-Positive and -Negative Breast Cancer.

    Science.gov (United States)

    Kerlikowske, Karla; Gard, Charlotte C; Tice, Jeffrey A; Ziv, Elad; Cummings, Steven R; Miglioretti, Diana L

    2017-05-01

    Risk factors may differentially influence development of estrogen receptor (ER)-positive vs -negative breast cancer. We examined associations with strong, prevalent risk factors by ER subtype. Of 1 279 443 women age 35 to 74 years participating in the Breast Cancer Surveillance Consortium, 14 969 developed ER-positive and 3617 developed ER-negative invasive breast cancer. We calculated hazard ratios (HRs) using Cox regression and compared ER subtype hazard ratios at representative ages or by menopausal status using Wald tests. All statistical tests were two-sided. For women age 40 years, compared with no prior biopsy, ER-positive vs ER-negative HRs were 1.53 (95% CI = 1.30 to 1.81) vs 1.26 (95% CI = 0.90 to 1.76) for nonproliferative disease, 1.63 (95% CI = 1.23 to 2.17) vs 1.41 (95% CI = 0.78 to 2.57) for proliferative disease without atypia, and 4.47 (95% CI = 2.88 to 6.96) vs 0.20 (95% CI = 0.02 to 2.51) for proliferative disease with atypia. Benign disease proliferation risk was stronger for ER-positive than ER-negative cancer for women age 35 years (Wald P = .04), age 40 years (Wald P = .04), and age 50 years (Wald P = .06). Among pre/perimenopausal women, body mass index (BMI) had a stronger association with ER-negative than ER-positive cancer (obese II/III vs. normal weight: HR = 1.52, 95% CI = 1.19 to 1.94; vs 1.21, 95% CI = 1.08 to 1.36). Increasing BMI similarly increased ER-positive and ER-negative cancer risk among postmenopausal hormone users (Wald P = .15) and nonusers (Wald P = .08). Associations with ER subtype varied by race/ethnicity across all ages (P breast cancer and breast density for specific ages. Strength of risk factor associations differed by ER subtype. Separate risk models for ER subtypes may improve identification of women for targeted prevention strategies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Arabidopsis ETR1 and ERS1 Differentially Repress the Ethylene Response in Combination with Other Ethylene Receptor Genes1[W

    Science.gov (United States)

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The ethylene response is negatively regulated by a family of five ethylene receptor genes in Arabidopsis (Arabidopsis thaliana). The five members of the ethylene receptor family can physically interact and form complexes, which implies that cooperativity for signaling may exist among the receptors. The ethylene receptor gene mutations etr1-1(C65Y)(for ethylene response1-1), ers1-1(I62P) (for ethylene response sensor1-1), and ers1C65Y are dominant, and each confers ethylene insensitivity. In this study, the repression of the ethylene response by these dominant mutant receptor genes was examined in receptor-defective mutants to investigate the functional significance of receptor cooperativity in ethylene signaling. We showed that etr1-1(C65Y), but not ers1-1(I62P), substantially repressed various ethylene responses independent of other receptor genes. In contrast, wild-type receptor genes differentially supported the repression of ethylene responses by ers1-1(I62P); ETR1 and ETHYLENE INSENSITIVE4 (EIN4) supported ers1-1(I62P) functions to a greater extent than did ERS2, ETR2, and ERS1. The lack of both ETR1 and EIN4 almost abolished the repression of ethylene responses by ers1C65Y, which implied that ETR1 and EIN4 have synergistic effects on ers1C65Y functions. Our data indicated that a dominant ethylene-insensitive receptor differentially repressed ethylene responses when coupled with a wild-type ethylene receptor, which supported the hypothesis that the formation of a variety of receptor complexes may facilitate differential receptor signal output, by which ethylene responses can be repressed to different extents. We hypothesize that plants can respond to a broad ethylene concentration range and exhibit tissue-specific ethylene responsiveness with differential cooperation of the multiple ethylene receptors. PMID:22227969

  10. Tamoxifen resistance and metastasis of human breast cancer cells were mediated by the membrane-associated estrogen receptor ER-α36 signaling in vitro.

    Science.gov (United States)

    Gu, Wenwen; Dong, Nian; Wang, Peng; Shi, Changgen; Yang, Jun; Wang, Jian

    2017-04-01

    The drug resistance and tumor metastasis have been the main obstacles for the longer-term therapeutic effects of tamoxifen (TAM) on estrogen receptor-positive (ER+) breast cancer, but the mechanisms underlying the TAM resistance are still unclear. Here, we demonstrated that the membrane-associated estrogen receptor ER-α36 signaling, but not the G protein-coupled estrogen receptor 1 (GPER1) signaling, might be involved in the TAM resistance and metastasis of breast cancer cells. In this study, a model of ER+ breast cancer cell MCF-7 that involves the up-regulated expression of ER-α36 and unchanged expression of ER-α66 and GPER1 was established via the removal of insulin from the cell culture medium. The mechanism of TAM resistance in the ER+ breast cancer cell line MCF-7 was investigated, and the results showed that the stimulating effect of insulin on susceptibility of MCF-7 to TAM was mediated by ER-α36 and that the expression level of ER-α36 in TAM-resistant MCF-7 cells was also significantly increased. Both TAM and estradiol (E2) could promote the migration of triple negative (ER-α66-/PR-/HER2-) and ER-α36+/GPER1+ breast cancer cells MDA-MB-231. The migration of MDA-MB-231 cells was inhibited by the down-regulated intracellular expression of ER-α36 by transient transfection of specific small interfering RNA, whereas no effect of GPER1 down-regulation was observed. Meanwhile, the effect of TAM on the migration of ER-α36-down-regulated MDA-MB-231 cells was also reduced. Furthermore, it was found that TAM enhanced the distribution of integrin β1 on the cell surface but did not affect the expression of integrin β1 in MDA-MB-231 cells. Collectively, these data suggested that ER-α36 signaling might play critical roles in acquired and de novo TAM resistance and metastasis of breast cancer, and ER-α36 might present a potential biomarker of TAM resistance in the clinical diagnosis and treatment of ER+ breast cancer.

  11. Lace plant ethylene receptors, AmERS1a and AmERS1c, regulate ethylene-induced programmed cell death during leaf morphogenesis.

    Science.gov (United States)

    Rantong, Gaolathe; Evans, Rodger; Gunawardena, Arunika H L A N

    2015-10-01

    The lace plant, Aponogeton madagascariensis, is an aquatic monocot that forms perforations in its leaves as part of normal leaf development. Perforation formation occurs through developmentally regulated programmed cell death (PCD). The molecular basis of PCD regulation in the lace plant is unknown, however ethylene has been shown to play a significant role. In this study, we examined the role of ethylene receptors during perforation formation. We isolated three lace plant ethylene receptors AmERS1a, AmERS1b and AmERS1c. Using quantitative PCR, we examined their transcript levels at seven stages of leaf development. Through laser-capture microscopy, transcript levels were also determined in cells undergoing PCD and cells not undergoing PCD (NPCD cells). AmERS1a transcript levels were significantly lower in window stage leaves (in which perforation formation and PCD are occurring) as compared to all other leaf developmental stages. AmERS1a and AmERS1c (the most abundant among the three receptors) had the highest transcript levels in mature stage leaves, where PCD is not occurring. Their transcript levels decreased significantly during senescence-associated PCD. AmERS1c had significantly higher transcript levels in NPCD compared to PCD cells. Despite being significantly low in window stage leaves, AmERS1a transcripts were not differentially expressed between PCD and NPCD cells. The results suggested that ethylene receptors negatively regulate ethylene-controlled PCD in the lace plant. A combination of ethylene and receptor levels determines cell fate during perforation formation and leaf senescence. A new model for ethylene emission and receptor expression during lace plant perforation formation and senescence is proposed.

  12. {sup 18}F-FDG-PET/CT for systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ulaner, Gary A.; Castillo, Raychel [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Wills, Jonathan [Memorial Sloan Kettering Cancer Center, Department of Information Systems, New York, NY (United States); Goenen, Mithat; Goldman, Debra A. [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States)

    2017-08-15

    This study assesses {sup 18}F-FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer. In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent {sup 18}F-FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.{sup 18}F-FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI). A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, {sup 18}F-FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9-20%). {sup 18}F-FDG-PET/CT revealed distant metastases in 14% (95% CI: 9-20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9-24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with {sup 18}F-FDG-PET/CT at the time of initial diagnosis. (orig.)

  13. Estrogen receptor-α36 is involved in epigallocatechin-3-gallate induced growth inhibition of ER-negative breast cancer stem/progenitor cells.

    Science.gov (United States)

    Pan, Xiaohua; Zhao, Bowen; Song, Zhen; Han, Shuai; Wang, Molin

    2016-02-01

    Epigallocatechin-3-gallate (EGCG) is a type of catechin extracted from green tea, which is reported to have anticancer effects. EGCG is also reported to inhibit the cancer stem/progenitor cells in several estrogen receptor (ER)-negative breast cancer cell lines, such as SUM-149, SUM-190 and MDA-MB-231. And all these cancer cells are highly expressed a new variant of ER-α, ER-α36. The aim of our present study is to determine the role of ER-α36 in the growth inhibitory activity of EGCG towards ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells. We found that EGCG potently inhibited the growth of cancer stem/progenitor cells in MDA-MB-231 and MDA-MB-436 cells, and also reduced the expression of ER-α36 in these cells. However, in ER-α36 knocked-down MDA-MB-231 and MDA-MB-436 cells, no significant inhibitory effects of EGCG on cancer stem/progenitor cells were observed. We also found that down-regulation of ER-α36 expression was in accordance with down-regulation of EGFR, which further verified a loop between ER-α36 and EGFR. Thus, our study indicated ER-α36 is involved in EGCG's inhibitory effects on ER-negative breast cancer stem/progenitor cells, which supports future preclinical and clinical evaluation of EGCG as a therapeutic option for ER-α36 positive breast cancer. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  14. Is breast cancer from Sub Saharan Africa truly receptor poor? Prevalence of ER/PR/HER2 in breast cancer from Kenya.

    Science.gov (United States)

    Sayed, Shahin; Moloo, Zahir; Wasike, Ronald; Bird, Peter; Oigara, Raymond; Govender, Dhirendra; Kibera, Joshua; Carrara, Henri; Saleh, Mansoor

    2014-10-01

    Studies on ER/PR/HER2 in breast cancer from Sub Saharan Africa (SSA) are fraught with inconsistencies in the prevalence of hormone receptor status. In Kenya, ER/PR/HER2 for breast cancers is not part of routine assessment and available in only three to four centers across the country. Variability in methodology and interpretation makes comparison between data difficult. Our aim was to accurately determine the prevalence of ER/PR/HER2 using standardized techniques and double reporting. Prognostic tumor parameters were also correlated with clinical features and receptor status. Consecutive invasive breast cancers (IBC) accrued between September 2011 and December 2012 were analyzed at Aga Khan University Hospital, Nairobi (AKUHN). Tumor blocks were stained for ER/PR/HER2 on an automated platform. Double reporting of ER/PR/HER2 was done using the Allred system and the ASCO/CAP guidelines respectively. A total of 301 cases of IBC were analyzed for pathology and ER/PR/HER2. The age range of patients was 19-94 years with a median of 47.5 years. Invasive ductal carcinoma (NOS) was the most common histologic type (84.2%). ER positivity was seen in 72.8%, PR in 64.8% and HER2 in 17.6% of all cases. Triple negative breast cancers (TNBC) constituted 20.2% of the cases. There was a significant association between receptor status and histologic grade (p prevalence of receptor status from SSA is comparable with that in the West. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. A transgenic mouse model expressing an ER? folding biosensor reveals the effects of Bisphenol A on estrogen receptor signaling

    OpenAIRE

    Sekar, Thillai V.; Foygel, Kira; Massoud, Tarik F.; Gambhir, Sanjiv S.; Paulmurugan, Ramasamy

    2016-01-01

    Estrogen receptor-? (ER?) plays an important role in normal and abnormal physiology of the human reproductive system by interacting with the endogenous ligand estradiol (E2). However, other ligands, either analogous or dissimilar to E2, also bind to ER?. This may create unintentional activation of ER signaling in reproductive tissues that can lead to cancer development. We developed a transgenic mouse model that constitutively expresses a firefly luciferase (FLuc) split reporter complementati...

  16. REEPs Are Membrane Shaping Adapter Proteins That Modulate Specific G Protein-Coupled Receptor Trafficking by Affecting ER Cargo Capacity

    OpenAIRE

    Susann Björk; Hurt, Carl M.; Ho, Vincent K.; Timothy Angelotti

    2013-01-01

    Receptor expression enhancing proteins (REEPs) were identified by their ability to enhance cell surface expression of a subset of G protein-coupled receptors (GPCRs), specifically GPCRs that have proven difficult to express in heterologous cell systems. Further analysis revealed that they belong to the Yip (Ypt-interacting protein) family and that some REEP subtypes affect ER structure. Yip family comparisons have established other potential roles for REEPs, including regulation of ER-Golgi t...

  17. 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.

  18. Proliferation of Estrogen Receptor alpha Positive Mammary Epithelial Cells is Restrained by TGFbeta1 in Adult Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ewan, Kenneth B.R.; Oketch-Rabah, Hellen A.; Ravani, Shraddha A.; Shyamala, G.; Moses, Harold L.; Barcellos-Hoff, Mary Helen

    2005-03-03

    Transforming growth factor {beta}1 (TGF{beta}1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor {alpha} (ER{alpha}) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF{beta}1 is necessary for the quiescence of ER{alpha}-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF{beta}1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF{beta} signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER{alpha}. To test whether TGF{beta} was functional, we examined genetically engineered mice with different levels of TGF{beta}1. ER{alpha} co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf{beta}1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF{beta}1 via the MMTV promoter suppressed proliferation of ER{alpha} positive cells. Thus, TGF{beta}1 activation functionally restrains ER{alpha} positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF{beta}1 dysregulation may promote proliferation of ER{alpha} positive cells associated with breast cancer risk in humans.

  19. Dormancy Signatures and Metastasis in Estrogen Receptor Positive and Negative Breast Cancer

    Science.gov (United States)

    Kim, Ryung S.; Avivar-Valderas, Alvaro; Estrada, Yeriel; Bragado, Paloma; Sosa, Maria Soledad; Aguirre-Ghiso, Julio A.; Segall, Jeffrey E.

    2012-01-01

    Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER) positive breast cell lines and primary tumors have significantly higher dormancy signature scores (P<0.0000001) than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS) compared to those whose tumors had high dormancy scores (HDS) (p<0.000005). The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines. PMID:22530051

  20. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Ryung S Kim

    Full Text Available Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER positive breast cell lines and primary tumors have significantly higher dormancy signature scores (P<0.0000001 than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS compared to those whose tumors had high dormancy scores (HDS (p<0.000005. The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines.

  1. A mouse model for Luminal epithelial like ER positive subtype of human breast cancer

    Directory of Open Access Journals (Sweden)

    Nagarajan P

    2007-09-01

    Full Text Available Abstract Background Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice. Methods Using brother-sister mating with pedigree expansion system, we derived a colony of heterozygous breeding females showing ER-Positive tumors around the age of 6 months. Complete blood picture, differential leukocyte count, and serum levels of Estrogen, Alanine amino transferase (SGPT, Aspartate amino transferase (SGOT, total protein and albumin were estimated. Aspiration biopsies and microbiology were carried out. Gross pathology of the tumors and their metastatic potential were assessed. The tumors were excised and further characterized using histopathology, cytology, electron microscopy (EM, molecular markers and Mouse mammary Tumor Virus – Long Terminal Repeats (MMTV LTR specific RT-PCR. Results The tumors originated from 2ndor 5thor both the mammary glands and were multi-nodulated with variable central necrosis accompanied with an accumulation of inflammatory exudate. Significant increases in estrogen, SGPT, SGOT and neutrophils levels were noticed. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and subcutaneous tissue. Metastatic spread through hematogenous and regional lymph nodes, into liver, lungs, spleen, heart and dermal lymphatics was observed. EM picture revealed no viral particles and MMTV-negativity was confirmed through MMTV LTR-specific RT-PCR. High expression of ER α, moderate to high expression of proliferating cell nuclear antigen (PCNA, moderate expression of vimentin and Cytokeratin 19 (K19 and low expression of p53 were observed in tumor sections, when compared with that of the normal mammary gland. Conclusion Since 75% of human breast cancer were classified ER-positive and as our model mimics (in most of the characteristics, such as histopathology, metastasis, high estrogen levels the ER-positive

  2. Minimising Immunohistochemical False Negative ER Classification Using a Complementary 23 Gene Expression Signature of ER Status

    DEFF Research Database (Denmark)

    Li, Qiyuan; Eklund, Aron Charles; Birkbak, Nicolai Juul

    2010-01-01

    BACKGROUND: Expression of the oestrogen receptor (ER) in breast cancer predicts benefit from endocrine therapy. Minimising the frequency of false negative ER status classification is essential to identify all patients with ER positive breast cancers who should be offered endocrine therapies...... subtypes as compared to IHC-based determination has not been systematically evaluated. Here we attempt to reduce the frequency of false negative ER status classification using two gene expression approaches and compare these methods to IHC based ER status in terms of predictive and prognostic concordance....../SIGNIFICANCE: Expression-based ER status classification may complement IHC to minimise false negative ER status classification and optimise patient stratification for endocrine therapies....

  3. Aryl hydrocarbon receptor (AhR) inducers and estrogen receptor (ER) activities in surface sediments of Three Gorges Reservoir, China evaluated with in vitro cell bioassays

    NARCIS (Netherlands)

    Wang, J.; Bovee, T.F.H.; Bi, Y.; Bernhöft, S.; Schramm, K.W.

    2014-01-01

    Two types of biological tests were employed for monitoring the toxicological profile of sediment cores in the Three Gorges Reservoir (TGR), China. In the present study, sediments collected in June 2010 from TGR were analyzed for estrogen receptor (ER)- and aryl hydrocarbon receptor (AhR)-mediated

  4. Identification and clinical implications of circulating microRNAs for estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Park, In Hae; Kang, Joo Hyun; Lee, Keun Seok; Nam, Seungyoon; Ro, Jungsil; Kim, Joo-Hang

    2014-12-01

    Cancer-associated microRNAs have been stably detected in blood. The objective of this study was to identify a panel of circulating microRNAs with the potential to serve as biomarkers for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2)- breast cancer. We used microarray-based expression profiling to compare the levels of circulating microRNAs in blood samples from 11 ER+/HER2- advanced breast cancer patients plus 5 age-matched controls. MicroRNA levels were validated by reverse transcription quantitative polymerase chain reaction in 40 control subjects, 187 early breast cancer patients, and 45 metastatic breast cancer patients. Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2- metastatic breast cancer. Initially, we found that miR-1280, miR-1260, and miR-720 were up-regulated in blood from breast cancer patients (P breast cancer patients and reflected tumor status (controlcancercancer). Among 37 metastatic breast cancer patients, miR-1280 levels significantly decreased after treatment in patients who responded to systemic treatment (P breast cancer patients and may serve as a biomarker for ER-positive breast cancer.

  5. REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity.

    Directory of Open Access Journals (Sweden)

    Susann Björk

    Full Text Available Receptor expression enhancing proteins (REEPs were identified by their ability to enhance cell surface expression of a subset of G protein-coupled receptors (GPCRs, specifically GPCRs that have proven difficult to express in heterologous cell systems. Further analysis revealed that they belong to the Yip (Ypt-interacting protein family and that some REEP subtypes affect ER structure. Yip family comparisons have established other potential roles for REEPs, including regulation of ER-Golgi transport and processing/neuronal localization of cargo proteins. However, these other potential REEP functions and the mechanism by which they selectively enhance GPCR cell surface expression have not been clarified. By utilizing several REEP family members (REEP1, REEP2, and REEP6 and model GPCRs (α2A and α2C adrenergic receptors, we examined REEP regulation of GPCR plasma membrane expression, intracellular processing, and trafficking. Using a combination of immunolocalization and biochemical methods, we demonstrated that this REEP subset is localized primarily to ER, but not plasma membranes. Single cell analysis demonstrated that these REEPs do not specifically enhance surface expression of all GPCRs, but affect ER cargo capacity of specific GPCRs and thus their surface expression. REEP co-expression with α2 adrenergic receptors (ARs revealed that this REEP subset interacts with and alter glycosidic processing of α2C, but not α2A ARs, demonstrating selective interaction with cargo proteins. Specifically, these REEPs enhanced expression of and interacted with minimally/non-glycosylated forms of α2C ARs. Most importantly, expression of a mutant REEP1 allele (hereditary spastic paraplegia SPG31 lacking the carboxyl terminus led to loss of this interaction. Thus specific REEP isoforms have additional intracellular functions besides altering ER structure, such as enhancing ER cargo capacity, regulating ER-Golgi processing, and interacting with select cargo

  6. REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity.

    Science.gov (United States)

    Björk, Susann; Hurt, Carl M; Ho, Vincent K; Angelotti, Timothy

    2013-01-01

    Receptor expression enhancing proteins (REEPs) were identified by their ability to enhance cell surface expression of a subset of G protein-coupled receptors (GPCRs), specifically GPCRs that have proven difficult to express in heterologous cell systems. Further analysis revealed that they belong to the Yip (Ypt-interacting protein) family and that some REEP subtypes affect ER structure. Yip family comparisons have established other potential roles for REEPs, including regulation of ER-Golgi transport and processing/neuronal localization of cargo proteins. However, these other potential REEP functions and the mechanism by which they selectively enhance GPCR cell surface expression have not been clarified. By utilizing several REEP family members (REEP1, REEP2, and REEP6) and model GPCRs (α2A and α2C adrenergic receptors), we examined REEP regulation of GPCR plasma membrane expression, intracellular processing, and trafficking. Using a combination of immunolocalization and biochemical methods, we demonstrated that this REEP subset is localized primarily to ER, but not plasma membranes. Single cell analysis demonstrated that these REEPs do not specifically enhance surface expression of all GPCRs, but affect ER cargo capacity of specific GPCRs and thus their surface expression. REEP co-expression with α2 adrenergic receptors (ARs) revealed that this REEP subset interacts with and alter glycosidic processing of α2C, but not α2A ARs, demonstrating selective interaction with cargo proteins. Specifically, these REEPs enhanced expression of and interacted with minimally/non-glycosylated forms of α2C ARs. Most importantly, expression of a mutant REEP1 allele (hereditary spastic paraplegia SPG31) lacking the carboxyl terminus led to loss of this interaction. Thus specific REEP isoforms have additional intracellular functions besides altering ER structure, such as enhancing ER cargo capacity, regulating ER-Golgi processing, and interacting with select cargo proteins

  7. Tumour 18 F-FDG Uptake on preoperative PET/CT may predict axillary lymph node metastasis in ER-positive/HER2-negative and HER2-positive breast cancer subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin You; Lee, Suck Hong; Kim, Suk [Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Department of Radiology, Seo-gu, Busan (Korea, Republic of); Kang, Taewoo [Pusan National University Hospital, Busan Cancer Center, Busan (Korea, Republic of); Bae, Young Tae [Pusan National University Hospital, Department of Surgery, Busan (Korea, Republic of)

    2015-04-01

    To evaluate the association between tumour FDG uptake on preoperative PET/CT and axillary lymph node metastasis (ALNM) according to breast cancer subtype. The records of 671 patients with invasive breast cancer who underwent {sup 18} F-FDG PET/CT and surgery were reviewed. Using immunohistochemistry, tumours were divided into three subtypes: oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive, and triple-negative. Tumour FDG uptake, expressed as maximum standardized uptake value (SUV{sub max}), and clinicopathological variables were analysed. ALNM was present in 187 of 461 ER-positive/HER2-negative, 54 of 97 HER2-positive, and 38 of 113 triple-negative tumours. On multivariate analysis, high tumour SUV{sub max} (≥4.25) (P < 0.001), large tumour size (>2 cm) (P = 0.003) and presence of lymphovascular invasion (P < 0.001) were independent variables associated with ALNM. On subset analyses, tumour SUV{sub max} maintained independent significance for predicting ALNM in ER-positive/HER2-negative (adjusted odds ratio: 3.277, P < 0.001) and HER2-positive tumours (adjusted odds ratio: 14.637, P = 0.004). No association was found for triple-negative tumours (P = 0.161). Tumour SUV{sub max} may be an independent prognostic factor for ALNM in patients with invasive breast cancer, especially in ER-positive/HER2-negative and HER2-positive subtypes, but not in those with triple-negative subtype. (orig.)

  8. Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells

    Science.gov (United States)

    Bhalla, Pankaj; Yang, Ximing; Ugolkov, Andrey; Iwadate, Kenichi; Karseladze, Apollon; Budunova, Irina

    2012-01-01

    Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate, AR acts as an oncogene, and GR is a tumor suppressor. Recently, we found that non-steroidal phyto-chemical compound A (CpdA) is AR/GR modulator acting as anti-inflammatory anti-androgen. CpdA inhibits AR and prevents GR transactivation while enhancing GR transrepression. GR and AR are controlled by proteasomal degradation. We found that prolonged exposure of LNCaP, LNCaP-GR, DU145 and PC3 prostate carcinoma (PCa) cells to proteasome inhibitor Bortezomib (BZ) caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ differentially regulated GR/AR to cooperatively suppress PCa cell growth and survival and to induce endoplasmic reticulum stress (ERS). Importantly, CpdA+BZ differentially regulated GR-responsive genes. CpdA+BZ blocked activation of glucocorticoid-responsive pro-survival genes, including SGK1, but activated BZ-induced ERS-related genes BIP/HSPA5 and CHOP/GADD153. Using ChIP, we showed that SGK1, BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. We also found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC) and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy. PMID:22223138

  9. 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.

  10. Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism.

    Science.gov (United States)

    Dunlap, Tareisha L; Howell, Caitlin E; Mukand, Nita; Chen, Shao-Nong; Pauli, Guido F; Dietz, Birgit M; Bolton, Judy L

    2017-11-20

    Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women's health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE 1 , 4-MeOE 1 ) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 μg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE 1 /CYP1B1 > 2-MeOE 1 /CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE 1 . In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in "normal" vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially

  11. ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67.

    Science.gov (United States)

    Tuominen, Vilppu J; Ruotoistenmäki, Sanna; Viitanen, Arttu; Jumppanen, Mervi; Isola, Jorma

    2010-01-01

    Accurate assessment of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 is essential in the histopathologic diagnostics of breast cancer. Commercially available image analysis systems are usually bundled with dedicated analysis hardware and, to our knowledge, no easily installable, free software for immunostained slide scoring has been described. In this study, we describe a free, Internet-based web application for quantitative image analysis of ER, PR, and Ki-67 immunohistochemistry in breast cancer tissue sections. The application, named ImmunoRatio, calculates the percentage of positively stained nuclear area (labeling index) by using a color deconvolution algorithm for separating the staining components (diaminobenzidine and hematoxylin) and adaptive thresholding for nuclear area segmentation. ImmunoRatio was calibrated using cell counts defined visually as the gold standard (training set, n = 50). Validation was done using a separate set of 50 ER, PR, and Ki-67 stained slides (test set, n = 50). In addition, Ki-67 labeling indexes determined by ImmunoRatio were studied for their prognostic value in a retrospective cohort of 123 breast cancer patients. The labeling indexes by calibrated ImmunoRatio analyses correlated well with those defined visually in the test set (correlation coefficient r = 0.98). Using the median Ki-67 labeling index (20%) as a cutoff, a hazard ratio of 2.2 was obtained in the survival analysis (n = 123, P = 0.01). ImmunoRatio was shown to adapt to various staining protocols, microscope setups, digital camera models, and image acquisition settings. The application can be used directly with web browsers running on modern operating systems (e.g., Microsoft Windows, Linux distributions, and Mac OS). No software downloads or installations are required. ImmunoRatio is open source software, and the web application is publicly accessible on our website. We anticipate that free web applications, such as ImmunoRatio, will make the

  12. 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.

  13. 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

  14. 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

  15. 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...

  16. 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...

  17. Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

    Science.gov (United States)

    2017-08-23

    Hormone Receptor Positive Malignant Neoplasm of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Metastatic Breast Cancer

  18. Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis.

    Science.gov (United States)

    Trukhacheva, Elena; Lin, Zhihong; Reierstad, Scott; Cheng, You-Hong; Milad, Magdy; Bulun, Serdar E

    2009-02-01

    Estradiol and its nuclear receptors, estrogen receptor (ER) alpha and ERbeta, play critical roles in endometrium and endometriosis. Levels of ERbeta, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ERalpha levels are lower in endometriosis. Estradiol regulates ERalpha gene expression via its alternatively used promoters A, B, and C. The aim of the study was to determine whether high levels of ERbeta in endometriotic stromal cells from ovarian endometriomas regulate ERalpha gene expression. ERbeta knockdown significantly increased ERalpha mRNA and protein levels in endometriotic stromal cells. Conversely, ERbeta overexpression in endometrial stromal cells decreased ERalpha mRNA and protein levels. ERbeta knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ERbeta binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ERalpha gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells. High levels of ERbeta suppress ERalpha expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ERalpha promoters. ERbeta also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ERbeta:ERalpha in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ERbeta may serve as a significant therapeutic target for endometriosis.

  19. Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study.

    Science.gov (United States)

    Ritte, Rebecca; Lukanova, Annekatrin; Tjønneland, Anne; Olsen, Anja; Overvad, Kim; Mesrine, Sylvie; Fagherazzi, Guy; Dossus, Laure; Teucher, Birgit; Steindorf, Karen; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Grioni, Sara; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Quirós, José Ramón; Buckland, Genevieve; Molina-Montes, Esther; Chirlaque, María-Dolores; Ardanaz, Eva; Amiano, Pilar; Bueno-de-Mesquita, Bas; van Duijnhoven, Franzel; van Gils, Carla H; Peeters, Petra Hm; Wareham, Nick; Khaw, Kay-Tee; Key, Timothy J; Travis, Ruth C; Krum-Hansen, Sanda; Gram, Inger Torhild; Lund, Eiliv; Sund, Malin; Andersson, Anne; Romieu, Isabelle; Rinaldi, Sabina; McCormack, Valerie; Riboli, Elio; Kaaks, Rudolf

    2013-06-01

    Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.08-1.20]) had a stronger risk association than leg length (1.05[1.00-1.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (≤13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and -negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women. Copyright © 2012 UICC.

  20. LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Schwarz, Luis J; Fox, Emily M; Balko, Justin M; Garrett, Joan T; Kuba, María Gabriela; Estrada, Mónica Valeria; González-Angulo, Ana María; Mills, Gordon B; Red-Brewer, Monica; Mayer, Ingrid A; Abramson, Vandana; Rizzo, Monica; Kelley, Mark C; Meszoely, Ingrid M; Arteaga, Carlos L

    2014-12-01

    Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.

  1. Effect of Monochromatic Light on Expression of Estrogen Receptor (ER and Progesterone Receptor (PR in Ovarian Follicles of Chicken.

    Directory of Open Access Journals (Sweden)

    Lingbin Liu

    Full Text Available Artificial illumination is widely used in modern poultry houses and different wavelengths of light affect poultry production and behaviour. In this study, we measure mRNA and protein abundance of estrogen receptors (ERs and progesterone receptors (PRs in order to investigate the effect of monochromatic light on egg production traits and gonadal hormone function in chicken ovarian follicles. Five hundred and fifty-two 19-wk-old laying hens were exposed to three monochromatic lights: red (RL; 660 nm, green (GL; 560 nm, blue (BL; 480 nm and control cool white (400-760 nm light with an LED (light-emitting diode. There were 4 identical light-controlled rooms (n = 138 each containing 3 replicate pens (46 birds per pen. Water was supplied ad libitum and daily rations were determined according to the nutrient suggestions for poultry. Results showed that under BL conditions there was an increase in the total number of eggs at 300 days of age and egg-laying rate during the peak laying period. The BL and GL extended the duration of the peak laying period. Plasma melatonin was lowest in birds reared under BL. Plasma estradiol was elevated in the GL-exposed laying hens, and GL and BL increased progesterone at 28 wk of age. In the granulosa layers of the fifth largest preovulatory follicle (F5, the third largest preovulatory follicle (F3 and the largest preovulatory follicle (F1, ERα mRNA was increased by BL and GL. Treatment with BL increased ERβ mRNA in granulosa layers of F5, F3 and F1, while GL increased ERβ mRNA in F5 and F3. There was a corresponding increase in abundance of the proteins in the granulosa layers of F5, with an increase in PR-B, generated via an alternative splice site, relative to PR-A. Treatment with BL also increased expression of PR mRNA in all of the granulosa layers of follicles, while treatment with GL increased expression of PR mRNA in granulosa layers of SYF(small yellow follicle, F5 and F1. These results indicate that blue

  2. The role of estrogen receptor {beta} (ER{beta}) in malignant diseases-A new potential target for antiproliferative drugs in prevention and treatment of cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warner, Margaret [Center for BioSciences, Department of BioSciences and Nutrition, Karolinska Institutet, Stockholm (Sweden); Center for Nuclear Receptors and Cell Signaling, Department of Biochemistry and Cell Biology, University of Houston, Houston, TX (United States); Gustafsson, Jan-Ake, E-mail: jan-ake.gustafsson@mednut.ki.se [Center for BioSciences, Department of BioSciences and Nutrition, Karolinska Institutet, Stockholm (Sweden); Center for Nuclear Receptors and Cell Signaling, Department of Biochemistry and Cell Biology, University of Houston, Houston, TX (United States)

    2010-05-21

    The discovery of ER{beta} in the middle of the 1990s represents a paradigm shift in our understanding of estrogen signaling. It has turned out that estrogen action is not mediated by one receptor, ER{alpha}, but by two balancing factors, ER{alpha} and ER{beta}, which are often antagonistic to one another. Excitingly, ER{beta} has been shown to be widespread in the body and to be involved in a multitude of physiological and pathophysiological events. This has led to a strong interest of the pharmaceutical industry to target ER{beta} by drugs against various diseases. In this review, focus is on the role of ER{beta} in malignant diseases where the anti proliferative activity of ER{beta} gives hope of new therapeutic approaches.

  3. Genome-wide association studies identify four ER negative-specific breast cancer risk loci

    NARCIS (Netherlands)

    Garcia-Closas, Montserrat; Couch, Fergus J.; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K.; Brook, Mark N.; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather S.; Le Marchand, Loic; Buring, Julie E.; Eccles, Diana; Miron, Penelope; Fasching, Peter A.; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K.; Nevanlinna, Heli; Giles, Graham G.; Cox, Angela; Hopper, John L.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J.; Schoof, Nils; Bojesen, Stig E.; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L.; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J.; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S.; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H.; Radice, Paolo; teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C.; Park, Daniel J.; Hammet, Fleur; Stone, Jennifer; Veer, Laura J. Van't; Rutgers, Emiel J.; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G.; Ekici, Arif B.; Beckmann, Matthias W.; dos Santos Silva, Isabel; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N.; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Balleine, Rosemary; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O.; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E.; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Coetzee, Gerhard A.; Feng, Ye; Henderson, Brian E.; Schumacher, Fredrick; Bogdanova, Natalia V.; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A. E. M.; Seynaeve, Caroline M.; Kriege, Mieke; Hooning, Maartje J.; van den Ouweland, Ans M. W.; van Deurzen, Carolien H. M.; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P.; Cross, Simon S.; Reed, Malcolm W. R.; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B.; Bandera, Elisa V.; John, Esther M.; Chen, Gary K.; Hu, Jennifer J.; Rodriguez-Gil, Jorge L.; Bernstein, Leslie; Press, Michael F.; Ziegler, Regina G.; Millikan, Robert M.; Deming-Halverson, Sandra L.; Nyante, Sarah; Ingles, Sue A.; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K.; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G.; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G.; Montgomery, Grant W.; Slamon, Dennis J.; Rauh, Claudia; Lux, Michael P.; Jud, Sebastian M.; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H.; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N.; Chen, Constance; Beck, Andy; Hankinson, Susan E.; Berg, Christine D.; Hoover, Robert N.; Lissowska, Jolanta; Figueroa, Jonine D.; Chasman, Daniel I.; Gaudet, Mia M.; Diver, W. Ryan; Willett, Walter C.; Hunter, David J.; Simard, Jacques; Benitez, Javier; Dunning, Alison M.; Sherman, Mark E.; Chenevix-Trench, Georgia; Chanock, Stephen J.; Hall, Per; Pharoah, Paul D. P.; Vachon, Celine; Easton, Douglas F.; Haiman, Christopher A.; Kraft, Peter

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including

  4. Genome-wide association studies identify four ER negative-specific breast cancer risk loci

    DEFF Research Database (Denmark)

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including...

  5. The estrogen receptor negative-progesterone receptor positive breast carcinoma is a biological entity and not a technical artifact.

    Science.gov (United States)

    Ng, Char Hong; Pathy, Nirmala Bhoo; Taib, Nur Aishah; Mun, Kein Seong; Rhodes, Anthony; Yip, Cheng Har

    2012-01-01

    The ER-/PR+ breast tumor may be the result of a false ER negative result. The aim of this study was to investigate whether there is a difference in patient and tumor characteristics of the ER-/PR+ phenotype in an Asian setting. A total of 2629 breast cancer patients were categorized on the basis of their age, ethnicity, tumor hormonal receptor phenotype, grade and histological type. There were 1230 (46.8%) ER+/PR+, 306 (11.6%) ER+/PR-, 122 (4.6%) ER-/PR+ and 972 (37%) ER-/PR-. ER-/PR+ tumors were 2.5 times more likely to be younger than 50 years at diagnosis (OR: 2.52; 95% CI: 1.72-3.67). Compared to ER+/PR+ tumors, the ER-/ PR+ phenotype was twice more likely to be associated with grade 3 tumors (OR:2.02; 95%CI: 1.00-4.10). In contrast, compared to ER-/PR- tumors, the ER-/PR+ phenotype was 90% less likely to be associated with a grade 3 tumor (OR: 0.12; 95%CI:0.05-0.26), and more likely to have invasive lobular than invasive ductal histology (OR: 3.66; 95%CI: 1.47-9.11). These results show that the ER-/PR+ phenotype occurs in a younger age group and is associated with intermediate histopathological characteristics compared to ER+/PR+ and ER-/PR- tumors. This may imply that it is a distinct entity and not a technical artifact.

  6. Disruption of the ER-α36-EGFR/HER2 Positive Regulatory Loops Restores Tamoxifen Sensitivity in Tamoxifen Resistance Breast Cancer Cells

    OpenAIRE

    Yin, Li; Zhang, Xin-Tian; Bian, Xiu-Wu; Guo, Yu-Ming; Wang, Zhao-Yi

    2014-01-01

    Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, most breast tumors develop tamoxifen resistance and are eventually refractory to tamoxifen therapy. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-α36, a variant of ER-α, were resistant to tamoxifen and knockdown of ER-α36 expression in tamoxifen resistant cells with the s...

  7. Neuroprotective Effects of Dexmedetomidine against Thapsigargin-induced ER-stress via Activity of α2-adrenoceptors and Imidazoline Receptors

    Directory of Open Access Journals (Sweden)

    Manami Inagaki

    2016-07-01

    Full Text Available Dexmedetomidine is a potent and highly selective α2-adrenoceptor agonist with sedative, analgesic, and sympatholytic properties, though it also exhibits some affinity for imidazoline binding sites. In addition to its sedative effects, dexmedetomidine exerts neuroprotective effects under ischemic conditions. Invasive incidents such as ischemia or hypoxia induce dysfunctions in energy production or depletion of ATP as well as accumulation and aggregation of abnormal proteins in the endoplasmic reticulum (ER, leading to an ER-stress response. In the present study, we examined whether dexmedetomidine exerts inhibitory effects on apoptosis mediated by thapsigargin-induced ER-stress in SH-SY5Y cells, and proposed a possible underlying mechanism for its neuroprotective effects. We used thapsigargin (TG to generate an ER-stress response in SH-SY5Y cells. SH-SY5Y cells were pretreated with Dex (1–1000 nM or receptor antagonists (atipamezole, efaroxan, BU99006, and 2’,5’-dideoxyadenosine for 1 hour before co-treatment with 1 mM TG for 20 hours. Co-incubation with dexmedetomidine suppressed thapsigargin-induced increases in cytosolic Ca2+, caspase-4 and -3 activity, eIF2α phosphorylation, and expression of ER-stress biomarkers. Dexmedetomidine treatment also decreased cAMP levels. In the presence of atipamezole or efaroxan, but not BU99006, inhibition of eIF2α phosphorylation and CHOP expression significantly increased following treatment with dexmedetomidine in thapsigargin-treated cells. However, pretreatment with BU99006 enhanced the increase in mitochondrial membrane potential associated with dexmedetomidine treatment. The results of the present study demonstrate that dexmedetomidine at clinically relevant concentrations suppresses ER-stress-induced apoptosis in SH-SY5Y cells. Some neuroprotective effects of dexmedetomidine may be mediated by α2-adrenoceptor and I1- and I2-receptors.

  8. Palbociclib:CDK4/6 inhibition in the treatment of ER-positive breast cancer.

    Science.gov (United States)

    Owsley, J; Jimeno, A; Diamond, J R

    2016-02-01

    Maintaining cell-cycle control has become a mainstay in treatment for many cancers. Cell-cycle manipulation can be especially valuable in breast cancer tumor cells that will often express hormone receptors that are amenable to anti-hormone receptor-targeted therapies. Despite these treatments, patients often progress, leading to other targeted agents being investigated to help promote progression-free survival. Cyclin-dependent kinases (CDKs) have been identified as contributors in the process of cell division. Combining inhibitors of CDKs with traditional endocrine treatments has shown significant progression-free survival in patients with metastatic breast cancer. One such CDK inhibitor, palbociclib, has shown great promise in the treatment of hormone receptor-positive breast cancer. In this article we review the traditional hormonal treatments of breast cancer, how CDK inhibition is beneficial in the treatment of this disease, and the preclinical and clinical data supporting the use of this medication. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

  9. Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CA (H1047R) in HER2/ER-positive breast cancer.

    Science.gov (United States)

    Cheng, Feixiong; Zhao, Junfei; Hanker, Ariella B; Brewer, Monica Red; Arteaga, Carlos L; Zhao, Zhongming

    2016-12-01

    Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti-estrogen receptor (ER) agents in HER2 or ER positive (HER2(+)/ER(+)) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2(+)/ER(+) breast cancer would provide novel insights into elucidating resistance to anti-HER2/ER therapies. In this study, we systematically investigated the biological consequences of PIK3CA (H1047R) in HER2(+)/ER(+) breast cancer by uniquely incorporating mRNA transcriptomic data from The Cancer Genome Atlas and proteomic data from reverse-phase protein arrays. Our integrative bioinformatics analyses revealed that several important pathways such as STAT3 and VEGF/hypoxia were selectively altered by PIK3CA (H1047R) in HER2(+)/ER(+) breast cancer. Protein differential expression analysis indicated that an elevated eIF4G might promote tumor angiogenesis and growth via regulation of the hypoxia-activated switch in HER2(+) PIK3CA (H1047R) breast cancer. We observed hypo-phosphorylation of EGFR in HER2(+) PIK3CA (H1047R) breast cancer versus HER2(+)PIK3CA(wild-type) (PIK3CA (WT)). In addition, ER and PIK3CA (H1047R) might cooperate to activate STAT3, MAPK, AKT, and Hippo pathways in ER(+) PIK3CA (H1047R) breast cancer. A higher YAPpS127 level was observed in ER(+) PIK3CA (H1047R) patients than that in an ER(+) PIK3CA (WT) subgroup. By examining breast cancer cell lines having both microarray gene expression and drug treatment data from the Genomics of Drug Sensitivity in Cancer and the Stand Up to Cancer datasets, we found that the elevated YAP1 mRNA expression was associated with the resistance of BCL-2 family inhibitors, but with the sensitivity to MEK/MAPK inhibitors in breast cancer cells. In summary, these findings shed light on the functional consequences of PIK3CA (H1047R)-driven breast

  10. Epidermal growth factor induces WISP-2/CCN5 expression in estrogen receptor-alpha-positive breast tumor cells through multiple molecular cross-talks.

    Science.gov (United States)

    Banerjee, Snigdha; Sengupta, Krishanu; Saxena, Neela K; Dhar, Kakali; Banerjee, Sushanta K

    2005-03-01

    Epidermal growth factor (EGF) is a mitogen for estrogen receptor (ER)-positive breast tumor cells, and it has been proven that EGF occasionally mimicked estrogen action and cross-talks with ER-alpha to exert its activity. Therefore, the present study was undertaken to explore whether EGF is able to modulate the expression of Wnt-1-induced signaling protein-2/connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed 5 (WISP-2/CCN5), an estrogen-responsive gene, in normal and transformed cell lines of the human breast and, if so, whether this induction is critical for EGF mitogenesis and what downstream signaling pathways are associated with this event. Here, we show that EGF-induced WISP-2 expression in ER- and EGF receptor-positive noninvasive MCF-7 breast tumor cells was dose and time dependent and that expression was modulated at transcription level. A synergism was seen in combination with estrogen. Moreover, small interfering RNA-mediated inhibition of WISP-2/CCN5 activity in MCF-7 cells resulted in abrogation of proliferation by EGF. The multiple molecular cross-talks, including the interactions between phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways and two diverse receptors (i.e., ER-alpha and EGFR), were essential in the event of EGF-induced WISP-2/CCN5 up-regulation in MCF-7 cells. Moreover, EGF action on WISP-2/CCN5 is restricted to ER- and EGFR-positive noninvasive breast tumor cells, and this effect of EGF cannot be instigated in ER-alpha-negative and EGFR-positive normal or invasive breast tumor cells by introducing ER-alpha. Finally, regulation of phosphorylation of ER-alpha and EGFR may play critical roles in EGF-induced transcriptional activation of WISP-2 gene in breast tumor cells.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Estrogen receptor (ER)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression.

    Science.gov (United States)

    Drew, Brian G; Hamidi, Habib; Zhou, Zhenqi; Villanueva, Claudio J; Krum, Susan A; Calkin, Anna C; Parks, Brian W; Ribas, Vicent; Kalajian, Nareg Y; Phun, Jennifer; Daraei, Pedram; Christofk, Heather R; Hewitt, Sylvia C; Korach, Kenneth S; Tontonoz, Peter; Lusis, Aldons J; Slamon, Dennis J; Hurvitz, Sara A; Hevener, Andrea L

    2015-02-27

    Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Anti-cancer stem cell activity of a hedgehog inhibitor GANT61 in estrogen receptor-positive breast cancer cells.

    Science.gov (United States)

    Kurebayashi, Junichi; Koike, Yoshikazu; Ohta, Yusuke; Saitoh, Wataru; Yamashita, Tetsumasa; Kanomata, Naoki; Moriya, Takuya

    2017-05-01

    Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)-positive breast cancer cells. It has been suggested that the non-canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER-positive breast cancer cells. We studied anti-CSC activity of a non-canonical Hh inhibitor GANT61 in ER-positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER-positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti-cell growth and anti-CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER-positive cell lines. E2 increased the expression levels of glioma-associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1-S cell cycle retardation and increased apoptosis. GANT61 decreased the E2-induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2-induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti-cell growth and/or anti-CSC activities in some ER-positive cell lines. In conclusion, the non-canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER-positive breast cancer cells. GANT61 enhanced anti-cell growth and/or anti-CSC activities of antiestrogens in ER-positive cell lines. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. Clinicopathologic Characteristics of Oestrogen Receptor-Positive/Progesterone Receptor-Negative/Her2-Negative Breast Cancer According to a Novel Definition of Negative Progesterone Receptor Status: A Large Population-Based Study from China.

    Directory of Open Access Journals (Sweden)

    An-qi Li

    Full Text Available A lack of progesterone receptor (PgR expression in oestrogen receptor-positive (ER+ tumours is associated with worse survival. PgR status is usually defined as positive or negative using 1% positive nuclei as a cut-off point. In this study, we aimed to assess the clinicopathologic characteristics of ER+/PgR-/HER2- tumours by comparing them with ER+/PgR+/HER2- tumours using a PgR cut-off point of 20% as a divisive criterion.We analysed 1,522 patients with primary breast cancer who had undergone surgery at the Cancer Center of Fudan University between 2012 and 2014. Age, grade, tumour size, lymph node status and lymphovascular invasion were assessed. Multinomial logistic regression, linear regression and chi-square test models were applied to assess associations between ER, PR and clinical features.ER+/PgR-/HER2- tumours showed poorer clinicopathologic characteristics relative to ER+/PgR+/HER2- tumours using a PgR threshold of 20% instead of 1%. The clinicopathologic characteristics did not differ between tumours with purely negative PgR expression and tumours with a PgR percentage ranging from 1% to 19%. The prognostic significance of PR expression appeared more pronounced in patients under a high Ki-67 status than those under a low Ki-67 status.Based on these findings, we propose the use of a novel threshold of 20% to define PgR status. Nevertheless, the impact of this new criterion on patient management and clinical treatment requires additional study.

  15. A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study.

    Science.gov (United States)

    Novelli, Flavia; Milella, Michele; Melucci, Elisa; Di Benedetto, Anna; Sperduti, Isabella; Perrone-Donnorso, Raffaele; Perracchio, Letizia; Venturo, Irene; Nisticò, Cecilia; Fabi, Alessandra; Buglioni, Simonetta; Natali, Pier Giorgio; Mottolese, Marcella

    2008-01-01

    Estrogen receptor-alpha (ER-alpha) and progesterone receptor (PgR) are consolidated predictors of response to hormonal therapy (HT). In contrast, little information regarding the role of estrogen receptor-beta (ER-beta) in various breast cancer risk groups treated with different therapeutic regimens is available. In particular, there are no data concerning ER-beta distribution within the novel molecular breast cancer subtypes luminal A (LA) and luminal B (LB), HER2 (HS), and triple-negative (TN). We conducted an observational prospective study using immunohistochemistry to evaluate ER-beta expression in 936 breast carcinomas. Associations with conventional biopathological factors and with molecular subtypes were analyzed by multiple correspondence analysis (MCA), while univariate and multivariate Cox regression analysis and classification and regression tree analysis were applied to determine the impact of ER-beta on disease-free survival in the 728 patients with complete follow-up data. ER-beta evenly distributes (55.5%) across the four molecular breast cancer subtypes, confirming the lack of correlation between ER-beta and classical prognosticators. However, the relationships among the biopathological factors, analyzed by MCA, showed that ER-beta positivity is located in the quadrant containing more aggressive phenotypes such as HER2 and TN or ER-alpha/PgR/Bcl2- tumors. Kaplan-Meier curves and Cox regression analysis identified ER-beta as a significant discriminating factor for disease-free survival both in the node-negative LA (P = 0.02) subgroup, where it is predictive of response to HT, and in the node-positive LB (P = 0.04) group, where, in association with PgR negativity, it conveys a higher risk of relapse. Our data indicated that, in contrast to node-negative patients, in node-positive breast cancer patients, ER-beta positivity appears to be a biomarker related to a more aggressive clinical course. In this context, further investigations are necessary to

  16. Factors Associated with the Use of Gene Expression Profiles in Estrogen Receptor-Positive Early-Stage Breast Cancer Patients: A Nationwide Study

    NARCIS (Netherlands)

    Kuijer, A.; Schreuder, Kay; Elias, S.G.; Smorenburg, C.H.; Rutgers, E.J.T.; Siesling, Sabine; van Dalen, T.

    2016-01-01

    Background: Breast cancer guidelines suggest the use of gene expression profiles (GEPs) in estrogen receptor-positive (ER+) breast cancer patients in whom controversy exists regarding adjuvant chemotherapy benefit based on traditional prognostic factors alone. We evaluated the current use of GEPs in

  17. Factors Associated with the Use of Gene Expression Profiles in Estrogen Receptor-Positive Early-Stage Breast Cancer Patients : A Nationwide Study

    NARCIS (Netherlands)

    Kuijer, Anne; Schreuder, Kay; Elias, Sjoerd G|info:eu-repo/dai/nl/261632590; Smorenburg, Carolien H; Rutgers, Emiel J T; Siesling, Sabine; van Dalen, Thijs

    2016-01-01

    BACKGROUND: Breast cancer guidelines suggest the use of gene expression profiles (GEPs) in estrogen receptor-positive (ER+) breast cancer patients in whom controversy exists regarding adjuvant chemotherapy benefit based on traditional prognostic factors alone. We evaluated the current use of GEPs in

  18. 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

  19. Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women.

    Science.gov (United States)

    Dunbier, Anita K; Anderson, Helen; Ghazoui, Zara; Folkerd, Elizabeth J; A'hern, Roger; Crowder, Robert J; Hoog, Jeremy; Smith, Ian E; Osin, Peter; Nerurkar, Ashutosh; Parker, Joel S; Perou, Charles M; Ellis, Matthew J; Dowsett, Mitch

    2010-03-01

    PURPOSE To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)-positive breast cancers in postmenopausal women. Materials and METHODS Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = -0.179; P = .05; and r = -0.389; P = .0005, respectively). CONCLUSION Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

  20. Epstein-Barr virus-kodet BILF1 er en konstitutivt aktiv G-protein-koblede receptor

    DEFF Research Database (Denmark)

    Paulsen, Sarah J; Rosenkilde, Mette M; Eugen-Olsen, Jesper

    2005-01-01

    Både beta-og gammaherpesviruses kode G-protein-koblede receptorer (GPCRs) med unikke farmakologiske fænotyper og vigtige biologiske funktioner. Et eksempel er ORF74, den gamma2-herpesvirus Kaposis sarkom-associated herpesvirus (KSHV)-kodet GPCR, som er meget konstitutivt aktiv og betragtes som den...... væsentligste Oncogene i Kaposis sarkom patogenese. I modsætning hertil den nuværende annotation af Epstein-Barr virus (EBV) genom ikke afslører nogen GPCR homolog kodet af denne menneskelige onkogene gamma1-herpesvirus. Men, ved at anvende bioinformatik, anerkendte vi, at den tidligere fastsatte EBV åben...... læsning ramme BILF1 faktisk koder en GPCR. Desuden BILF1 er medlem af en ny familie af beslægtede GPCRs udelukkende kodet af gamma1-herpesviruses. Angivelse af hæmagglutinin-mærkede BILF1 i HEK293 epitelcelle linje viste, at BILF1 udtrykkes som en cirka 50-kDa glykosyleret protein. Immunhistokemi og...

  1. Breast density and parenchymal texture measures as potential risk factors for estrogen-receptor positive breast cancer

    Science.gov (United States)

    Keller, Brad M.; Chen, Jinbo; Conant, Emily F.; Kontos, Despina

    2014-03-01

    Accurate assessment of a woman's risk to develop specific subtypes of breast cancer is critical for appropriate utilization of chemopreventative measures, such as with tamoxifen in preventing estrogen-receptor positive breast cancer. In this context, we investigate quantitative measures of breast density and parenchymal texture, measures of glandular tissue content and tissue structure, as risk factors for estrogen-receptor positive (ER+) breast cancer. Mediolateral oblique (MLO) view digital mammograms of the contralateral breast from 106 women with unilateral invasive breast cancer were retrospectively analyzed. Breast density and parenchymal texture were analyzed via fully-automated software. Logistic regression with feature selection and was performed to predict ER+ versus ER- cancer status. A combined model considering all imaging measures extracted was compared to baseline models consisting of density-alone and texture-alone features. Area under the curve (AUC) of the receiver operating characteristic (ROC) and Delong's test were used to compare the models' discriminatory capacity for receptor status. The density-alone model had a discriminatory capacity of 0.62 AUC (p=0.05). The texture-alone model had a higher discriminatory capacity of 0.70 AUC (p=0.001), which was not significantly different compared to the density-alone model (p=0.37). In contrast the combined density-texture logistic regression model had a discriminatory capacity of 0.82 AUC (pmeasures may have the potential to identify women specifically at risk for estrogen-receptor positive breast cancer and could be useful in triaging women into appropriate risk-reduction strategies.

  2. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience.

    Science.gov (United States)

    Ciccarese, Mariangela; Fabi, Alessandra; Moscetti, Luca; Cazzaniga, Maria Elena; Petrucelli, Luciana; Forcignanò, Rosachiara; Lupo, Laura Isabella; De Matteis, Elisabetta; Chiuri, Vincenzo Emanuele; Cairo, Giuseppe; Febbraro, Antonio; Giordano, Guido; Giampaglia, Marianna; Bilancia, Domenico; La Verde, Nicla; Maiello, Evaristo; Morritti, Maria; Giotta, Francesco; Lorusso, Vito; Latorre, Agnese; Scavelli, Claudio; Romito, Sante; Cusmai, Antonio; Palmiotti, Gennaro; Surico, Giammarco

    2017-06-01

    This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

  3. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

    Science.gov (United States)

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-08-01

    The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37) for the worst prognosis (ER-/PR-) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Zahra Rasoulzadeh

    Full Text Available 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.

  6. Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers.

    Science.gov (United States)

    Watanabe, Takahiro; Hida, Akira I; Inoue, Natsuko; Imamura, Michiko; Fujimoto, Yukie; Akazawa, Kouhei; Hirota, Seiichi; Miyoshi, Yasuo

    2017-11-22

    The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2-) BC is still controversial. We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2- BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2- BCs. A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2- BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2- cases with a high TIL score also tended to achieve pCR (p = 0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2- BC (p = 0.034). Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2- BC.

  7. Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Fuentes-Mattei, Enrique; Velazquez-Torres, Guermarie; Phan, Liem; Zhang, Fanmao; Chou, Ping-Chieh; Shin, Ji-Hyun; Choi, Hyun Ho; Chen, Jiun-Sheng; Zhao, Ruiying; Chen, Jian; Gully, Chris; Carlock, Colin; Qi, Yuan; Zhang, Ya; Wu, Yun; Esteva, Francisco J; Luo, Yongde; McKeehan, Wallace L; Ensor, Joe; Hortobagyi, Gabriel N; Pusztai, Lajos; Fraser Symmans, W; Lee, Mong-Hong; Yeung, Sai-Ching Jim

    2014-07-01

    Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon. We analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV-TGFα;A (y) /a) and orthotopic/syngeneic (A (y) /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided. Functional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial-mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro. Adipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity. © The Author 2014. Published by Oxford University Press.

  8. The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer.

    Science.gov (United States)

    Krishnan, Aruna V; Swami, Srilatha; Feldman, David

    2012-09-01

    Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+BCa in women. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Prognostic Discrimination Using a 70-Gene Signature among Patients with Estrogen Receptor-Positive Breast Cancer and an Intermediate 21-Gene Recurrence Score

    Directory of Open Access Journals (Sweden)

    Sung Gwe Ahn

    2013-12-01

    Full Text Available The Oncotype DX® recurrence score (RS predictor has been clinically utilized to appropriately select adjuvant chemotherapy for patients with estrogen receptor (ER-positive early breast cancer. However, the selection of chemotherapy for patients with intermediate RSs remains controversial. We assessed the prognostic value of a 70-gene signature (70GS among patients with ER-positive breast cancer and intermediate RSs. In addition, we sought to identify genes associated with poor 70GS scores based on gene expression profiling (GEP. GEP was performed using gene expression data from 186 patients with ER-positive breast cancer. The RS and 70GS score were calculated on the basis of GEP. Among 186 patients, 82 ER-positive patients with intermediate RSs were identified. These patients were stratified by 70GS, overall survival (OS significantly differed according to 70GS (p = 0.013. In a supervised hierarchical analysis according to 70GS, the expression of several representative genes for cell proliferation was significantly higher in the poor 70GS cluster than in the good 70GS cluster. Furthermore, among these patients, FOXM1, AURKA, AURKB, and BIRC5 displayed prognostic significance for OS. In conclusion, 70GS can help to discriminate survival differences among ER-positive patients with intermediate RSs. FOXM1, AURKA, AURKB, and BIRC5, are associated with poor 70GS scores.

  10. Post-Transcriptional Regulation of Chemokine Receptor CXCR4 by Estrogen in HER2 Overexpressing, Estrogen Receptor-Positive Breast Cancer Cells

    Science.gov (United States)

    Sengupta, Surojeet; Schiff, Rachel; Katzenellenbogen, Benita S.

    2008-01-01

    Expression of the chemokine receptor CXCR4, a G protein-coupled receptor, and HER2, a receptor tyrosine kinase, strongly correlates with the aggressive and metastatic potential of breast cancer cells. We studied estrogen regulation of CXCR4 in estrogen receptor (ER)-positive MCF-7 breast cancer cells overexpressing HER2 (MCF7-HER2). Although estrogen evoked no change in CXCR4 mRNA levels, CXCR4 protein was significantly up-regulated after estrogen treatment of these cells, whereas estrogen had no effect on CXCR4 protein level in parental MCF7 cells that are low in HER2. Use of the CXCR4 specific inhibitor, AMD 3100, indicated that this increase in CXCR4 protein was partially responsible for the increase in estrogen-induced migration of these cells. The estrogen-induced increase in CXCR4 protein in MCF-7-HER2 cells was abrogated by the antiestrogen ICI 182780 and by gefitinib (Iressa; a phosphotyrosine kinase inhibitor), indicating an ER-mediated effect and confirming involvement of receptor tyrosine kinases, respectively. Using specific pathway inhibitors, we show that the estrogen-induced increase in CXCR4 involves PI3K/AKT, MAPK and mTOR pathways. PI3K/AKT and MAPK pathways are known to result in the phosphorylation and functional inactivation of tuberin (TSC2) of tuberous sclerosis complex thereby negating its inhibitory effects on mTOR, which in turn stimulates the translational machinery. Small interfering RNA (siRNA) mediated knockdown of tuberin elevated the level of CXCR4 protein in MCF7-HER2 cells and also nullified further estrogen up-regulation of CXCR4. This study suggests a pivotal role of PI3K, MAPK and mTOR pathways, via tuberin, in post-transcriptional control of CXCR4, initiated through estrogen-stimulated crosstalk between ER and HER2. Thus, post-transcriptional regulation of CXCR4 by estrogens acting through ER via kinase pathways may play a critical role in determining the metastatic potential of breast cancer cells. PMID:18807177

  11. Low Concordance between Gene Expression Signatures in ER Positive HER2 Negative Breast Carcinoma Could Impair Their Clinical Application.

    Directory of Open Access Journals (Sweden)

    Enora Laas

    Full Text Available Numerous prognostic gene expression signatures have been recently described. Among the signatures there is variation in the constituent genes that are utilized. We aim to evaluate prognostic concordance among eight gene expression signatures, on a large dataset of ER positive HER2 negative breast cancers.We analysed the performance of eight gene expression signatures on six different datasets of ER+ HER2- breast cancers. Survival analyses were performed using the Kaplan-Meier estimate of survival function. We assessed discrimination and concordance between the 8 signatures on survival and recurrence rates The Nottingham Prognostic Index (NPI was used to to stratify the risk of recurrence/death.The discrimination ability of the whole signatures, showed fair discrimination performances, with AUC ranging from 0.64 (95%CI 0.55-0.73 for the 76-genes signatures, to 0.72 (95%CI 0.64-0.8 for the Molecular Prognosis Index T17. Low concordance was found in predicting events in the intermediate and high-risk group, as defined by the NPI. Low risk group was the only subgroup with a good signatures concordance.Genomic signatures may be a good option to predict prognosis as most of them perform well at the population level. They exhibit, however, a high degree of discordance in the intermediate and high-risk groups. The major benefit that we could expect from gene expression signatures is the standardization of proliferation assessment.

  12. Impact of palbociclib combinations on treatment of advanced estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer.

    Science.gov (United States)

    Boér, Katalin

    2016-01-01

    Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2)-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years. In 2012, a new molecularly targeted therapeutic strategy, inhibition of mammalian target of rapamycin with everolimus, was introduced into clinical practice. Everolimus, in combination with a steroidal aromatase inhibitor, exemestane, resulted in an increase in progression-free survival, but not overall survival in patients with estrogen receptor (ER)+ve advanced disease who had progressed on hormone therapy. In 2015, the first cyclin-dependent kinases 4/6 (CDK4/6) inhibitor, palbociclib, received accelerated US Food and Drug Administration approval for use in combination with letrozole for the treatment of postmenopausal ER+ve/HER2-ve advanced breast cancer as initial, endocrine-based therapy. The addition of palbociclib to endocrine therapy resulted in longer progression-free survival than letrozole alone. One year later, palbociclib received a new indication, use in combination with fulvestrant, in both premenopausal and postmenopausal females with advanced breast cancer of the same subtype with disease progression following endocrine therapy. Adding palbociclib to fulvestrant resulted in a significantly increased median progression-free survival compared to fulvestrant monotherapy. These new combination regimens of palbociclib with endocrine agents represent an important addition

  13. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.

    Science.gov (United States)

    Turner, Nicholas C; Ro, Jungsil; André, Fabrice; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Loibl, Sibylle; Huang Bartlett, Cynthia; Zhang, Ke; Giorgetti, Carla; Randolph, Sophia; Koehler, Maria; Cristofanilli, Massimo

    2015-07-16

    Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer. This phase 3 study involved 521 patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred. The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; Ppalbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone

  14. A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer.

    Science.gov (United States)

    Ma, Cynthia X; Suman, Vera; Goetz, Matthew P; Northfelt, Donald; Burkard, Mark E; Ademuyiwa, Foluso; Naughton, Michael; Margenthaler, Julie; Aft, Rebecca; Gray, Richard; Tevaarwerk, Amye; Wilke, Lee; Haddad, Tufia; Moynihan, Timothy; Loprinzi, Charles; Hieken, Tina; Barnell, Erica K; Skidmore, Zachary L; Feng, Yan-Yang; Krysiak, Kilannin; Hoog, Jeremy; Guo, Zhanfang; Nehring, Leslie; Wisinski, Kari B; Mardis, Elaine; Hagemann, Ian S; Vij, Kiran; Sanati, Souzan; Al-Kateb, Hussam; Griffith, Obi L; Griffith, Malachi; Doyle, Laurence; Erlichman, Charles; Ellis, Matthew J

    2017-09-05

    Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER(+)) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER(+) breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER(+) breast cancer.Experimental Design: Potential eligible patients with clinical stage II/III ER(+)/HER2(-) breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER(+) breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 1-10. ©2017 AACR. ©2017 American Association for Cancer Research.

  15. Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture

    Directory of Open Access Journals (Sweden)

    Marta Esteves da Silva

    2015-11-01

    Full Text Available Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing endosomes. In addition, how the positioning of AMPAR-containing endosomes affects synapse organization and functioning has never been directly explored. Here, we used live-cell imaging in hippocampal neuron cultures to show that intracellular AMPARs are transported in Rab11-positive recycling endosomes, which frequently enter dendritic spines and depend on the microtubule and actin cytoskeleton. By using chemically induced dimerization systems to recruit kinesin (KIF1C or myosin (MyosinV/VI motors to Rab11-positive recycling endosomes, we controlled their trafficking and found that induced removal of recycling endosomes from spines decreases surface AMPAR expression and PSD-95 clusters at synapses. Our data suggest a mechanistic link between endosome positioning and postsynaptic structure and composition.

  16. Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple-negative but not estrogen receptor-positive breast cancers.

    Science.gov (United States)

    Krishnamurti, Uma; Wetherilt, Ceyda Sonmez; Yang, Jing; Peng, Limin; Li, Xiaoxian

    2017-06-01

    Correlation between tumor-infiltrating lymphocytes (TILs) and complete pathological response (pCR) in breast cancers in neoadjuvant settings have been reported. In this study, we analyzed the association between TILs and diagnostic and prognostic parameters in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) without neoadjuvant treatments. Three hundred forty-four (344) patients who underwent mastectomy for breast cancer (187 ER+ and 157 TNBC) without neoadjuvant treatments were evaluated. Percentage of overall and peripheral TILs were correlated with lymphovascular invasion (LVI), Nottingham histologic grade (NHG, 1/2 versus 3), stage, lymph node status (LN), overall survival (OS), and disease-free survival (DFS). In TNBC, both peripheral and overall TILs were significantly associated with NHG 3 (PP=.0354) and DFS (HR: 0.95; 95% CI: 0.91-1.00; P=.0314) in univariate and multivariate analysis. In ER+ breast cancer, only peripheral TILs were associated with NHG 3 (P=.018) but not with OS or DFS (both P>.05). In ER+ breast cancer, there was a negative association between Oncotype DX recurrence score and both overall (P=.0007) and peripheral TILs (P=.0119). In conclusion, peripheral but not overall TILs correlate with better OS and DFS in TNBC, indicating the location of TILs may be important in TNBC. The negative association between TILs and Oncotype DX score in ER+ may indicate the possible prognostic value of TILs in ER+ breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

    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...... propose that iHBECERpos may serve to shed light on hitherto unappreciated differences in ER regulation and function between normal breast and breast cancer....

  18. 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.

  19. Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress.

    Science.gov (United States)

    Leclerc, Guy J; DeSalvo, Joanna; Du, Jianfeng; Gao, Ningguo; Leclerc, Gilles M; Lehrman, Mark A; Lampidis, Theodore J; Barredo, Julio C

    2015-08-20

    BCR-ABL positive (+) acute lymphoblastic leukemia (ALL) accounts for ∼30% of cases of ALL. We recently demonstrated that 2-deoxy-d-glucose (2-DG), a dual energy (glycolysis inhibition) and ER-stress (N-linked-glycosylation inhibition) inducer, leads to cell death in ALL via ER-stress/UPR-mediated apoptosis. Among ALL subtypes, BCR-ABL+ ALL cells exhibited the highest sensitivity to 2-DG suggesting BCR-ABL expression may be linked to this increased vulnerability. To confirm the role of BCR-ABL, we constructed a NALM6/BCR-ABL stable cell line and found significant increase in 2-DG-induced apoptosis compared to control. We found that Mcl-1 was downregulated by agents inducing ER-stress and Mcl-1 levels correlated with ALL sensitivity. In addition, we showed that Mcl-1 expression is positively regulated by the MEK/ERK pathway, dependent on BCR-ABL, and further downregulated by combining ER-stressors with TKIs. We determined that energy/ER stressors led to translational repression of Mcl-1 via the AMPK/mTOR and UPR/PERK/eIF2α pathways. Taken together, our data indicate that BCR-ABL+ ALL exhibits heightened sensitivity to induction of energy and ER-stress through inhibition of the MEK/ERK pathway, and translational repression of Mcl-1 expression via AMPK/mTOR and UPR/PERK/eIF2α pathways. This study supports further consideration of strategies combining energy/ER-stress inducers with BCR-ABL TKIs for future clinical translation in BCR-ABL+ ALL patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer.

    Science.gov (United States)

    Jansen, Valerie M; Bhola, Neil E; Bauer, Joshua A; Formisano, Luigi; Lee, Kyung-Min; Hutchinson, Katherine E; Witkiewicz, Agnieszka K; Moore, Preston D; Estrada, Mónica Valéria; Sánchez, Violeta; Ericsson, Paula G; Sanders, Melinda E; Pohlmann, Paula R; Pishvaian, Michael J; Riddle, David A; Dugger, Teresa C; Wei, Wenyi; Knudsen, Erik S; Arteaga, Carlos L

    2017-05-01

    Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase in the levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E, and D1, activated phospho-CDK2, and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and to restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib, in combination with GSK2334470 or the PI3Kα inhibitor alpelisib, decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K-PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors. Cancer Res; 77(9); 2488-99. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Metastasis Dormancy in Estrogen Receptor-Positive Breast Cancer

    Science.gov (United States)

    Zhang, Xiang H.-F.; Giuliano, Mario; Trivedi, Meghana V.; Schiff, Rachel; Kent Osborne, C.

    2013-01-01

    About 20-40% of breast cancer patients eventually develop recurrences in distant organs, which are often not detected until years to decades after the primary tumor diagnosis. This phenomenon is especially pronounced in ER+ breast cancer, suggesting that ER+ cancer cells may stay dormant for a protracted period of time, despite adjuvant therapies. Multiple mechanisms have been proposed to explain how cancer cells survive and remain in dormancy , and how they become reactivated and exit dormancy. These mechanisms include angiogenic switch, immunosurveillance, and interaction with extracellular matrix (ECM) and stromal cells. How to eradicate or suppress these dormant cancer cells remains a major clinical issue because of the lack of knowledge about the biological and clinical nature of these cells. Herein, we review the clinical manifestation of metastasis dormancy in ER+ tumors, the current biological insights of tumor dormancy obtained from various experimental models, and the clinical challenges to predict, detect, and treat dormant metastases. We also discuss future research directions toward a better understanding of the biological mechanisms and clinical management of ER+ dormant metastasis. PMID:24298069

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

    Science.gov (United States)

    Ahn, Sung Gwe; Lee, Jae-Hoon; Lee, Hak Woo; Jeon, Tae Joo; Ryu, Young Hoon; Kim, Kun Min; Sohn, Joohyuk; Yun, Mijin; Lee, Seung Ah; Jeong, Joon; Kim, Seung Il

    2017-01-01

    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 reverse transcriptase-polymerase chain reaction, and SUV (Pearson's R = -0.408; P 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.

  3. Insulin-like growth factor-1 (IGF-1) induces WISP-2/CCN5 via multiple molecular cross-talks and is essential for mitogenic switch by IGF-1 axis in estrogen receptor-positive breast tumor cells.

    Science.gov (United States)

    Dhar, Kakali; Banerjee, Snigdha; Dhar, Gopal; Sengupta, Krishanu; Banerjee, Sushanta K

    2007-02-15

    Previously, we have shown that the expression of Wnt-1-induced signaling protein-2 (WISP-2), also known as CCN5, can be regulated by multiple stimulants in estrogen receptor (ER)-positive breast tumor cells to exert their mitogenic action in these cells. Here, we show that insulin-like growth factor-1 (IGF-1), a strong mitogen, enhanced the expression of the WISP-2/CCN5 gene parallel with the induction of proliferation of ER-positive breast tumor cells. An additive effect was also seen in combination with estrogen. Perturbation of IGF-1-induced WISP-2/CCN5 expression by WISP-2-specific RNA interference impaired the mitogenic action of IGF-1 on ER-positive breast tumor cells. Furthermore, the studies have shown that the multiple molecular cross-talks and side-talks among IGF-1R, ER-alpha, and phosphatidylinositol 3-kinase (PI3K)/Akt signaling molecules are required to induce WISP-2/CCN5 mRNA by IGF-1 in ER-positive, noninvasive breast tumor cells. Because a pure anti-ER ICI 182,780 is not only able to suppress the up-regulation of WISP-2/CCN5 mRNA expression by IGF-1, it also suppresses the PI3K/Akt activity induced by IGF-1 in MCF-7 cells; we anticipate that the membrane ER receptor may participate in this event. Collectively, these studies propose for the first time that WISP-2/CCN5 is an integral signaling molecule in mitogenic action of IGF-1 axis in ER-positive human breast tumor cells.

  4. The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.

    Science.gov (United States)

    Hong, Cynthia; Duit, Sarah; Jalonen, Pilvi; Out, Ruud; Scheer, Lilith; Sorrentino, Vincenzo; Boyadjian, Rima; Rodenburg, Kees W; Foley, Edan; Korhonen, Laura; Lindholm, Dan; Nimpf, Johannes; van Berkel, Theo J C; Tontonoz, Peter; Zelcer, Noam

    2010-06-25

    We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.

  5. The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2*

    Science.gov (United States)

    Hong, Cynthia; Duit, Sarah; Jalonen, Pilvi; Out, Ruud; Scheer, Lilith; Sorrentino, Vincenzo; Boyadjian, Rima; Rodenburg, Kees W.; Foley, Edan; Korhonen, Laura; Lindholm, Dan; Nimpf, Johannes; van Berkel, Theo J. C.; Tontonoz, Peter; Zelcer, Noam

    2010-01-01

    We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism. PMID:20427281

  6. Transcription factor Brn-3α mRNA in cancers, relationship with AR, ER receptors and AKT/m-TOR pathway components

    Science.gov (United States)

    Spirina, L. V.; Gorbunov, A. K.; Chigevskaya, S. Y.; Usynin, Y. A.; Kondakova, I. V.; Slonimskaya, E. M.; Usynin, E. A.; Choinzonov, E. L.; Zaitseva, O. S.

    2017-09-01

    Transcription factors POU4F1 (neurogenic factor Brn-3α) play a pivotal role in cancers development. The aim of the study was to reveal the Brn-3α expression, AR, ER expression in cancers development, association with AKT/mTOR pathway activation. 30 patients with locally advanced prostate cancer, 20 patients with papillary thyroid cancer, T2-3N0-1M0 stages and 40 patients with renal cell cancer T2-3N0M0-1 were involved into the study. The expressions of Brn-3α, AR, ERα, components of AKT/m-TOR signaling pathway genes were performed by real-time PCR. The dependence of Brn-3α expression on mRNA levels of steroid hormone receptors and components of AKT/m-TOR signaling pathway in studied cancers were shown. High levels of mRNA of nuclear factor, steroid hormone receptors were found followed by the activation of this signaling pathway in prostate cancer tissue. The reduction of transcription factor Brn-3α was accompanied with tumor invasive growth with increasing rates of AR, ER and 4E-BP1 mRNA. Thyroid cancer development happened in a case of a Brn-3α and steroid hormone receptors decrease. The activation of AKT/m-TOR signaling pathway was established in the metastatic renal cancers, accompanied with the increase of ER mRNA. But there was no correlation between the steroid receptor and Brn-3α. One-direction changes of Brn-3α were observed in the development of prostate and thyroid cancer due to its effect on the steroid hormone receptors and the activation of AKT/m-TOR signaling pathway components. The influence of this factor on the development of the kidney cancer was mediated through m-TOR activity modifications, the key enzyme of oncogenesis.

  7. CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression.

    Science.gov (United States)

    Mitra, Partha; Yang, Ren-Ming; Sutton, James; Ramsay, Robert G; Gonda, Thomas J

    2016-02-23

    Our previous studies showed that MYB is required for proliferation of, and confers protection against apoptosis on, estrogen receptor-positive (ER(+ve)) breast cancer cells, which are almost invariably also MYB(+ve). We have also shown that MYB expression in ER(+ve) breast cancer cells is regulated at the level of transcriptional elongation and as such, is suppressed by CDK9i. Here we examined the effects of CDK9i on breast cancer cells and the involvement of MYB in these effects. ER(+ve) breast cancer cell lines including MCF-7 were much more sensitive (> 10 times) to killing by CDK9i than ER(-ve)/MYB(-ve) cells. Moreover, surviving cells showed a block at the G2/M phase of the cell cycle. Importantly, ectopic MYB expression conferred resistance to apoptosis induction, cell killing and G2/M accumulation. Expression of relevant MYB target genes including BCL2 and CCNB1 was suppressed by CDK9 inhibition, and this too was reversed by ectopic MYB expression. Nevertheless, inhibition of BCL2 alone either by MYB knockdown or by ABT-199 treatment was insufficient for significant induction of apoptosis. Further studies implied that suppression of MCL-1, a well-documented target of CDK9 inhibition, was additionally required for apoptosis induction, while maximal levels of apoptosis induced by CDK9i are likely to also involve inhibition of BCL2L1 expression. Taken together these data suggest that MYB regulation of BCL2 underlies the heightened sensitivity of ER(+ve) compared to ER(-ve) breast cancer cells to CDK9 inhibition, and that these compounds represent a potential therapeutic for ER(+ve) breast cancers and possibly other MYB-dependent cancers.

  8. NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

    Directory of Open Access Journals (Sweden)

    Ambs Stefan

    2010-05-01

    Full Text Available Abstract Background A recent genome-wide association study (GWAS has identified a single nucleotide polymorphism (SNP rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER+ versus ER- cancer. Results We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059. In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG of rs11249433 when compared to the non-risk AA genotype (p = 0.0062. Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015, but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. Conclusion This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.

  9. Pushing estrogen receptor around in breast cancer.

    Science.gov (United States)

    Lim, Elgene; Tarulli, Gerard; Portman, Neil; Hickey, Theresa E; Tilley, Wayne D; Palmieri, Carlo

    2016-12-01

    The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER. © 2016 Society for Endocrinology.

  10. Impact of palbociclib combinations on treatment of advanced estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Boér K

    2016-10-01

    Full Text Available Katalin Boér Department of Medical Oncology, Szent Margit Hospital, Budapest, Hungary Abstract: Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years. In 2012, a new molecularly targeted therapeutic strategy, inhibition of mammalian target of rapamycin with everolimus, was introduced into clinical practice. Everolimus, in combination with a steroidal aromatase inhibitor, exemestane, resulted in an increase in progression-free survival, but not overall survival in patients with estrogen receptor (ER+ve advanced disease who had progressed on hormone therapy. In 2015, the first cyclin-dependent kinases 4/6 (CDK4/6 inhibitor, palbociclib, received accelerated US Food and Drug Administration approval for use in combination with letrozole for the treatment of postmenopausal ER+ve/HER2-ve advanced breast cancer as initial, endocrine-based therapy. The addition of palbociclib to endocrine therapy resulted in longer progression-free survival than letrozole alone. One year later, palbociclib received a new indication, use in combination with fulvestrant, in both premenopausal and postmenopausal females with advanced breast cancer of the same subtype with disease progression following endocrine therapy. Adding palbociclib to fulvestrant resulted in a significantly increased median progression-free survival compared to fulvestrant

  11. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study.

    Science.gov (United States)

    Arpino, Grazia; Green, Stephanie J; Allred, D Craig; Lew, Dannika; Martino, Silvana; Osborne, C Kent; Elledge, Richard M

    2004-09-01

    Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen. Three hundred and forty nine patients had estrogen receptor (ER)-positive breast cancer and received daily tamoxifen as initial therapy for advanced disease. HER-2 gene amplification, detected by fluorescence in situ hybridization, and HER-1 expression, evaluated by immunohistochemistry, was determined on 136 and 204 patients, respectively. HER-2 amplification was correlated with lower ER (P = 0.02), HER-1 positivity (P = 0.004), and HER-2 protein overexpression (P HER-1-negative versus 36% for HER-1-positive (P = 0.05). Time to treatment failure (TTF) was 7 months for non-amplified HER-2 tumors and 5 months (P = 0.007) for amplified HER-2 tumors, and there was a trend toward a better overall survival (OS) in patients with non-amplified HER-2 tumors (median 31 versus 25 months, respectively, P = 0.07). For positive versus negative HER-1 tumors, TTF was 4 versus 8 months (P = 0.08) and median survival was 24 versus 31 months (P = 0.41). Combining HER-1 expression and HER-2 gene status, patients with both negative HER-1 expression and non-amplified HER-2 had longer TTF (P = 0.001) and OS (P = 0.03) than if either were positive. In multivariate analysis, HER-2 was not an independent factor for TTF and OS, although HER-1 was significant for TTF only (P HER-1 expression had lower ER levels and were modestly less responsive to tamoxifen, suggesting that molecular events in addition to those involving the ErbB receptors are important in determining the endocrine-resistant phenotype.

  12. Aryl hydrocarbon receptor (AhR) inducers and estrogen receptor (ER) activities in surface sediments of Three Gorges Reservoir, China evaluated with in vitro cell bioassays.

    Science.gov (United States)

    Wang, Jingxian; Bovee, Toine F H; Bi, Yonghong; Bernhöft, Silke; Schramm, Karl-Werner

    2014-02-01

    Two types of biological tests were employed for monitoring the toxicological profile of sediment cores in the Three Gorges Reservoir (TGR), China. In the present study, sediments collected in June 2010 from TGR were analyzed for estrogen receptor (ER)- and aryl hydrocarbon receptor (AhR)-mediated activities. The estrogenic activity was assessed using a rapid yeast estrogen bioassay, based on the expression of a green fluorescent reporter protein. Weak anti-estrogenic activity was detected in sediments from an area close to the dam of the reservoir, and weak estrogenic activities ranging from 0.3 to 1 ng 17β-estradiol (E2) equivalents (EQ) g(-1) dry weight sediment (dw) were detected in sediments from the Wanzhou to Guojiaba areas. In the upstream areas Wanzhou and Wushan, sediments demonstrated additive effects in co-administration of 1 nM E2 in the yeast test system, while sediments from the downstream Badong and Guojiaba areas showed estrogenic activities which seemed to be more than additive (synergistic activity). There was an increasing tendency in estrogenic activity from upstream of TGR to downstream, while this tendency terminated and converted into anti-estrogenic activity in the area close to the dam. The AhR activity was detected employing rat hepatoma cell line (H4IIE). EROD activities were found homogenously distributed in sediments in TGR ranging from 200 to 311 pg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) EQ g(-1) dw for total AhR agonists and from 45 to 76 pg TCDD EQ g(-1) dw for more persistent AhR agonists. The known AhR agonists polycyclic aromatic hydrocarbon, polychlorinated biphenyl, and PCDD/F only explained up to 8 % of the more persistent AhR agonist activity in the samples, which suggests that unidentified AhR-active compounds represented a great proportion of the TCDD EQ in sediments from TGR. These findings of estrogenic potential and dioxin-like activity in TGR sediments provide possible weight-of-evidence of potential

  13. Type-I Insulin-Like Growth Factor Receptor (IGF1R)-Estrogen Receptor (ER) Crosstalk Contributes to Antiestrogen Therapy Resistance in Breast Cancer Cells

    Science.gov (United States)

    2013-02-01

    consequences that can be treated using metformin (18). Thus, the clinical benefit of using lGFlR/IR tyrosine kinase inhibitors(TKI) may outweigh their...d IG F-JJ-stimu la ted proliferation in MCF-7L and T47D (data not shown) cells a nd insu lin and I G F-ll -stimu lated proli feration in...opausal women wit h horm one-receptor positive (HR +) metastat ic (M) or locally advanced ( LA ) breast cancer (BC). Cancer Res 2010;70:76s

  14. Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas

    Directory of Open Access Journals (Sweden)

    Soini Ylermi

    2011-06-01

    Full Text Available Abstract Background Triple-negative breast cancer (TNBC and basal-like breast cancer (BLBC are breast cancer subtypes with an especially poor prognosis. 8-Hydroxydeoxyguanosine (8-OHdG is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2 and Kelch-like ECH-associated protein 1 (Keap1 are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC. Methods We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression. Control cases (n = 42 were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1. Results Patients with TNBC had worse breast cancer-specific survival (BCSS than the control group (p = 0.015. Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p vs. the non-TNBC group (p = 0.022. Conclusions Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC.

  15. Excessive signal transduction of gain-of-function variants of the calcium-sensing receptor (CaSR are associated with increased ER to cytosol calcium gradient.

    Directory of Open Access Journals (Sweden)

    Marianna Ranieri

    Full Text Available In humans, gain-of-function mutations of the calcium-sensing receptor (CASR gene are the cause of autosomal dominant hypocalcemia or type 5 Bartter syndrome characterized by an abnormality of calcium metabolism with low parathyroid hormone levels and excessive renal calcium excretion. Functional characterization of CaSR activating variants has been so far limited at demonstrating an increased sensitivity to external calcium leading to lower Ca-EC50. Here we combine high resolution fluorescence based techniques and provide evidence that for the efficiency of calcium signaling system, cells expressing gain-of-function variants of CaSR monitor cytosolic and ER calcium levels increasing the expression of the Sarco-Endoplasmic Reticulum Calcium-ATPase (SERCA and reducing expression of Plasma Membrane Calcium-ATPase (PMCA. Wild-type CaSR (hCaSR-wt and its gain-of-function (hCaSR-R990G; hCaSR-N124K variants were transiently transfected in HEK-293 cells. Basal intracellular calcium concentration was significantly lower in cells expressing hCaSR-wt and its gain of function variants compared to mock. In line, FRET studies using the D1ER probe, which detects [Ca2+]ER directly, demonstrated significantly higher calcium accumulation in cells expressing the gain of function CaSR variants compared to hCaSR-wt. Consistently, cells expressing activating CaSR variants showed a significant increase in SERCA activity and expression and a reduced PMCA expression. This combined parallel regulation in protein expression increases the ER to cytosol calcium gradient explaining the higher sensitivity of CaSR gain-of-function variants to external calcium. This control principle provides a general explanation of how cells reliably connect (and exacerbate receptor inputs to cell function.

  16. Excessive Signal Transduction of Gain-of-Function Variants of the Calcium-Sensing Receptor (CaSR) Are Associated with Increased ER to Cytosol Calcium Gradient

    Science.gov (United States)

    Di Mise, Annarita; Vezzoli, Giuseppe; Soldati, Laura; Svelto, Maria; Valenti, Giovanna

    2013-01-01

    In humans, gain-of-function mutations of the calcium-sensing receptor (CASR) gene are the cause of autosomal dominant hypocalcemia or type 5 Bartter syndrome characterized by an abnormality of calcium metabolism with low parathyroid hormone levels and excessive renal calcium excretion. Functional characterization of CaSR activating variants has been so far limited at demonstrating an increased sensitivity to external calcium leading to lower Ca-EC50. Here we combine high resolution fluorescence based techniques and provide evidence that for the efficiency of calcium signaling system, cells expressing gain-of-function variants of CaSR monitor cytosolic and ER calcium levels increasing the expression of the Sarco-Endoplasmic Reticulum Calcium-ATPase (SERCA) and reducing expression of Plasma Membrane Calcium-ATPase (PMCA). Wild-type CaSR (hCaSR-wt) and its gain-of-function (hCaSR-R990G; hCaSR-N124K) variants were transiently transfected in HEK-293 cells. Basal intracellular calcium concentration was significantly lower in cells expressing hCaSR-wt and its gain of function variants compared to mock. In line, FRET studies using the D1ER probe, which detects [Ca2+]ER directly, demonstrated significantly higher calcium accumulation in cells expressing the gain of function CaSR variants compared to hCaSR-wt. Consistently, cells expressing activating CaSR variants showed a significant increase in SERCA activity and expression and a reduced PMCA expression. This combined parallel regulation in protein expression increases the ER to cytosol calcium gradient explaining the higher sensitivity of CaSR gain-of-function variants to external calcium. This control principle provides a general explanation of how cells reliably connect (and exacerbate) receptor inputs to cell function. PMID:24244430

  17. Optimization of transmission-scan time for the FixER method: a MR-based PET attenuation correction with a weak fixed-position external radiation source

    Energy Technology Data Exchange (ETDEWEB)

    Kawaguchi, Hiroshi; Hirano, Yoshiyuki; Kershaw, Jeff; Yoshida, Eiji [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Shiraishi, Takahiro [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Suga, Mikio [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Center for Frontier Medical Engineering, Chiba University (Japan); Obata, Takayuki [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Ito, Hiroshi; Yamaya, Taiga [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan)

    2014-07-29

    In recent work, we proposed an MRI-based attenuation-coefficient (μ-value) estimation method that uses a weak fixed-position external radiation source to construct an attenuation map for PET/MRI. In this presentation we refer to this method as FixER, and perform a series of simulations to investigate the duration of the transmission scan required to accurately estimate μ-values.

  18. Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture

    NARCIS (Netherlands)

    Esteves da Silva, Marta; Adrian, Max|info:eu-repo/dai/nl/369490959; Schätzle, Philipp; Lipka, Joanna|info:eu-repo/dai/nl/369403142; Watanabe, Takuya; Cho, Sukhee; Futai, Kensuke; Wierenga, Corette J|info:eu-repo/dai/nl/237383292; Kapitein, Lukas C|info:eu-repo/dai/nl/298806630; Hoogenraad, Casper C|info:eu-repo/dai/nl/227263502

    2015-01-01

    Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs) at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing

  19. Factors affecting estrogen receptor status in a multiracial Asian country : An analysis of 3557 cases

    NARCIS (Netherlands)

    Yip, C. H.; Pathy, N. Bhoo; Uiterwaal, C. S.; Taib, N. A.; Tan, G. H.; Mun, K. S.; Choo, W. Y.; Rhodes, A.

    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.

  20. The Orphan Nuclear Receptor NR4A1 Protects Pancreatic β-Cells from Endoplasmic Reticulum (ER) Stress-mediated Apoptosis.

    Science.gov (United States)

    Yu, Cong; Cui, Shang; Zong, Chen; Gao, Weina; Xu, Tongfu; Gao, Peng; Chen, Jicui; Qin, Dandan; Guan, Qingbo; Liu, Yuantao; Fu, Yuchang; Li, Xia; Wang, Xiangdong

    2015-08-21

    The role of NR4A1 in apoptosis is controversial. Pancreatic β-cells often face endoplasmic reticulum (ER) stress under adverse conditions such as high free fatty acid (FFA) concentrations and sustained hyperglycemia. Severe ER stress results in β-cell apoptosis. The aim of this study was to analyze the role of NR4A1 in ER stress-mediated β-cell apoptosis and to characterize the related mechanisms. We confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the mRNA and protein levels of NR4A1 rapidly increased in both MIN6 cells and mouse islets. NR4A1 overexpression in MIN6 cells conferred resistance to cell loss induced by TG or PA, as assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and TUNEL assays indicated that NR4A1 overexpression also protected against ER stress-induced apoptosis. This conclusion was further confirmed by experiments exploiting siRNA to knockdown NR4A1 expression in MIN6 cells or exploiting NR4A1 knock-out mice. NR4A1 overexpression in MIN6 cells reduced C/EBP homologous protein (CHOP) expression and Caspase3 activation induced by TG or PA. NR4A1 overexpression in MIN6 cells or mouse islets resulted in Survivin up-regulation. A critical regulatory element was identified in Survivin promoter (-1872 bp to -1866 bp) with a putative NR4A1 binding site; ChIP assays demonstrated that NR4A1 physically associates with the Survivin promoter. In conclusion, NR4A1 protects pancreatic β-cells against ER stress-mediated apoptosis by up-regulating Survivin expression and down-regulating CHOP expression, which we termed as "positive and negative regulation." © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer.

    Science.gov (United States)

    Patel, Hetal; Abduljabbar, Rezvan; Lai, Chun-Fui; Periyasamy, Manikandan; Harrod, Alison; Gemma, Carolina; Steel, Jennifer H; Patel, Naina; Busonero, Claudia; Jerjees, Dena; Remenyi, Judit; Smith, Sally; Gomm, Jennifer J; Magnani, Luca; Győrffy, Balázs; Jones, Louise J; Fuller-Pace, Frances; Shousha, Sami; Buluwela, Laki; Rakha, Emad A; Ellis, Ian O; Coombes, R Charles; Ali, Simak

    2016-12-01

    CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics. mRNA and protein expression of CDK7 and its essential cofactors cyclin H and MAT1 were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathologic features and patient outcome. We show that expressions of CDK7, cyclin H, and MAT1 are all closely linked at the mRNA and protein level, and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumor grade and size, and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity. Expressions of components of the CAK complex, CDK7, MAT1, and Cyclin H are elevated in breast cancer and correlate with ER. Like ER, CDK7 expression is inversely proportional to poor prognostic factors and survival. Clin Cancer Res; 22(23); 5929-38. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Steroid hormone receptors in male breast diseases.

    Science.gov (United States)

    Pacheco, M M; Oshima, C F; Lopes, M P; Widman, A; Franco, E L; Brentani, M M

    1986-01-01

    Estrogen (ER), progesterone (PR), glucocorticoid (GR) and androgen (AR) receptors were assayed in tumor samples from 8 cases of male breast cancer (MBC) and 20 cases of male gynecomastia. Seven out of eight (87.5%) male tumor samples had positive ER assays with values ranging from 12 to 180 fmol/mg protein. Of the seven ER positive cases of MBC, six, had positive PR activity with high titers. Positive GR and AR values were also detected in 75% of MBC cases. Concentrations of all four receptors were significantly correlated with each other. With gynecomastic tissue, the proportion of receptor-positive patients was 20% ER, 20% PR, 20% AR, and 45% GR. Except for GR, steroid receptor values for MBC individuals were significantly higher than those of gynecomastia patients.

  3. [A case of effective trastuzumab plus gemcitabine therapy for human epidermal growth factor receptor 2-positive breast cancer].

    Science.gov (United States)

    Yabe, Nobushige; Murai, Shinji; Shimizu, Hirotomo; Kitasato, Kenjiro; Yoshikawa, Takahisa; Oto, Ippei; Nakadai, Junpei; Jinno, Hiromitsu; Kitagawa, Yuko

    2013-11-01

    A 71-year-old postmenopausal woman was undergoing treatment for depression. She visited the hospital with a chief complaint of fibrosclerosis of the entire left breast 8 years previously. She was diagnosed as having stage IV( T3N1M1b) left breast cancer (papillotubular>scirrhous carcinoma, g+, f+, estrogen receptor [ER]-negative, progesterone receptor [PgR]-negative, and human epidermal growth factor receptor 2[ HER2/neu]-positive[ 3+]). Synchronous bone metastases were detected in the left tenth rib, the eleventh dorsal vertebra, and in the area spanning the lower lumbar to sacral vertebrae. First-line treatment was systemic therapy with 4 cycles of Adriamycin and cyclophosphamide (AC) followed by 4 cycles of trastuzumab and paclitaxel. The breast mass initially observed on clinical imaging disappeared and only calcifications were observed. Bone metastases were detected only in the left tenth rib. As an additional therapy, 3-dimensional radiotherapy( 50 Gy/25 fractions), which irradiated the left mammary gland, axilla, and supraclavicular fossa, was administered. The tumor was well controlled for approximately 3 years. However, a gradual increase in the level of carcinoembryonic antigen( CEA) was accompanied by an increase in the left breast mass and enlargement of left axillary lymph nodes. Modified radical mastectomy (Bt+Ax [level I]) was performed for this condition 3 years ago. Papillotubular-type invasive ductal carcinoma (INF β, ly3, v0, g+, f+, s+, nuclear grade 3 [atypia 3+mitosis 3]) was diagnosed histopathologically. Lymph node metastases were also detected. As histopathological examination of the bone metastatic lesion showed no progression, administration of lapatinib and capecitabine was initiated. After 15 cycles of treatment, enlarged right axillary lymph nodes were observed and local excision was performed. Histopathological examination revealed recurrence of the breast cancer. The patient was diagnosed as having grade 3( atypia 3, mitosis 2

  4. Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist.

    Directory of Open Access Journals (Sweden)

    Mi-Kyung Kim

    Full Text Available Beta cell death caused by endoplasmic reticulum (ER stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1 reversed by exenatide, 2 exaggerated by exenatide, and 3 unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.

  5. Worse prognosis in breast cancer patients can be predicted by immunohistochemical analysis of positive MMP-2 and negative estrogen and progesterone receptors

    Directory of Open Access Journals (Sweden)

    Edneia A. S. Ramos

    Full Text Available Summary Introduction: Breast cancer is the most cause of death, and approximately 90% of these deaths are due to metastases. Matrix metalloproteinase-2 (MMP-2 gelatinase activity is able to degrade a major constituent of the tumor microenvironment, type IV collagen. Two well-established proteins used as markers in clinical practice for breast cancer are the receptors for estrogen (ER and progesterone (PR. Although the presence of these receptors has been associated with a better prognosis, loss of these proteins can occur during tumor progression, with subsequent resistance to hormone therapy. Objective: To study the correlation among MMP-2, ER, and PR, as well as the establishment of the metastatic process in primary breast tumors. Method: Breast cancer samples (n=44 were analyzed by immunohistochemistry for MMP-2, ER, and PR. Results: We observed that 90% of patients who had metastases and died showed positive staining for MMP-2 (p=0.0082 for both. Using Kaplan-Meier analysis, we found that negative ER patients who were also positive for MMP-2 had even worse disease-free survival (DFS and overall survival (OS (p= 0.012 and p=0.005, respectively. Similar results were found in PR-negative patients for DFS (a trend p=0.077 and OS (p=0.038. Conclusion: Regardless of our small sample size (n=44, the data obtained strongly suggest that MMP-2 in combination with already well-established markers could help to predict the emergence of metastases and death in patients with breast cancer.

  6. 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

    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...... design and the same qPCR profiling platform, resulting in limited agreement. CONCLUSIONS: A panel of 4 circulating miRNAs exhibited significantly altered levels following radical resection of primary ER+ breast cancers in post-menopausal women. These specific miRNAs may be involved in tumorigenesis...

  7. Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin.

    Science.gov (United States)

    Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

    2017-01-31

    Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.

  8. 25(OH) vitamin D suppresses macrophage adhesion and migration by downregulation of ER stress and scavenger receptor A1 in type 2 diabetes.

    Science.gov (United States)

    Riek, Amy E; Oh, Jisu; Darwech, Isra; Moynihan, Clare E; Bruchas, Robin R; Bernal-Mizrachi, Carlos

    2014-10-01

    Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). Vitamin D deficiency is not only more prevalent in diabetics but also doubles the risk of developing CVD. However, it is unknown whether 25-hydroxy vitamin D [25(OH)D3] replacement slows monocyte adhesion and migration, critical mechanisms involved in atherosclerosis progression. In this study, monocytes from vitamin D-deficient diabetic patients were cultured either in the patient's serum or in vitamin D-deficient media with or without 25(OH)D3 treatment. Adding 25(OH)D3 to monocytes cultured in vitamin D-deficient serum or media decreased monocyte adhesion to fibronectin and migration stimulated by monocyte chemotactic protein 1 (MCP-1). Accordingly, 25(OH)D3 decreased adhesion marker β1- and β2-integrin expression and migration receptor chemokine (C-C motif) receptor 2 (CCR2) expression. 25(OH)D3 treatment downregulated monocyte endoplasmic reticulum (ER) stress and scavenger receptor class A, type 1 (SR-A1) expression. The absence of SR-A1 prevented the increased macrophage adhesion and migration induced by vitamin D deficiency. Moreover, the absence of SR-A1 prevented the induction of adhesion and migration and expression of their associated membrane receptors by Thapsigargin, an ER stress inducer. These results identify cellular activation of monocyte/macrophage vitamin D signaling through 25(OH)D3 as a potential mechanism that could modulate adhesion and migration in diabetic subjects. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Reduced Insulin/Insulin-Like Growth Factor Receptor Signaling Mitigates Defective Dendrite Morphogenesis in Mutants of the ER Stress Sensor IRE-1.

    Directory of Open Access Journals (Sweden)

    Yehuda Salzberg

    2017-01-01

    Full Text Available Neurons receive excitatory or sensory inputs through their dendrites, which often branch extensively to form unique neuron-specific structures. How neurons regulate the formation of their particular arbor is only partially understood. In genetic screens using the multidendritic arbor of PVD somatosensory neurons in the nematode Caenorhabditis elegans, we identified a mutation in the ER stress sensor IRE-1/Ire1 (inositol requiring enzyme 1 as crucial for proper PVD dendrite arborization in vivo. We further found that regulation of dendrite growth in cultured rat hippocampal neurons depends on Ire1 function, showing an evolutionarily conserved role for IRE-1/Ire1 in dendrite patterning. PVD neurons of nematodes lacking ire-1 display reduced arbor complexity, whereas mutations in genes encoding other ER stress sensors displayed normal PVD dendrites, specifying IRE-1 as a selective ER stress sensor that is essential for PVD dendrite morphogenesis. Although structure function analyses indicated that IRE-1's nuclease activity is necessary for its role in dendrite morphogenesis, mutations in xbp-1, the best-known target of non-canonical splicing by IRE-1/Ire1, do not exhibit PVD phenotypes. We further determined that secretion and distal localization to dendrites of the DMA-1/leucine rich transmembrane receptor (DMA-1/LRR-TM is defective in ire-1 but not xbp-1 mutants, suggesting a block in the secretory pathway. Interestingly, reducing Insulin/IGF1 signaling can bypass the secretory block and restore normal targeting of DMA-1, and consequently normal PVD arborization even in the complete absence of functional IRE-1. This bypass of ire-1 requires the DAF-16/FOXO transcription factor. In sum, our work identifies a conserved role for ire-1 in neuronal branching, which is independent of xbp-1, and suggests that arborization defects associated with neuronal pathologies may be overcome by reducing Insulin/IGF signaling and improving ER homeostasis and

  10. Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors

    DEFF Research Database (Denmark)

    Larsen, Anja Probst; Fièvre, Sabine; Frydenvang, Karla

    2017-01-01

    Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of (...

  11. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance

    Science.gov (United States)

    Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R) are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and nega...

  12. [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.

  13. Detection of estrogen receptor endocrine disruptor potency of commonly used organochlorine pesticides using the LUMI-CELL ER bioassay

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, J.D.; Chu, A.C.; Clark, G.C. [Xenobiotic Detection Systems, Inc., Durham, NC (United States); Chu, M.D. [Alta Analytical Perspectives, Wilmington, NC (United States); Denison, M.S. [Dept. of Environmental Toxicology, Univ. of California, Davis, CA (United States)

    2004-09-15

    In order to detect the endocrine disrupting potency of organochlorine pesticides and other compounds, BG-1 (human ovarian carcinoma) cells containing a stably transfected estrogenresponsive luciferase reporter gene plasmid (BG1Luc4E2), was used. This cell line, termed the LUMI-CELL trademark ER estrogenic cell bioassay system, responds in a time-, dose dependent- and chemical-specific manner with the induction of luciferase gene expression in response to exposure to estrogen (but not other steroid hormones) and estrogenic chemicals in a high-throughput screening (HTPS) format6. Here we describe studies in which the LUMI-CELL trademark ER estrogenic cell bioassay system was used for high throughput screening (HTPS) analysis of the estrogenic disrupting potency of several commonly used pesticides and organochlorines: p,p'DDT; p,p'-DDE; DDD; {alpha}a-chlordane; {psi}-chlordane; Kepone; Methoxychlor; Vinclozolin; Fenarimol; 2,4,5-Trichlorophenoxyacetic Acid; and Dieldrin. Our results demonstrate the utility of XDS's LUMI-CELL trademark ER bioassay HTPS system for screening chemicals for estrogenic activity.

  14. Mucoadhesive Oral Wound Rinse in Preventing and Treating Stomatitis in Patients With ER- or PR-Positive Metastatic or Locally Recurrent Breast Cancer That Cannot be Removed by Surgery Receiving Everolimus

    Science.gov (United States)

    2017-04-25

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Oral Complications; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  15. Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells.

    Science.gov (United States)

    Thaler, Sonja; Schmidt, Marcus; Roβwag, Sven; Thiede, Gitta; Schad, Arno; Sleeman, Jonathan P

    2017-09-22

    Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) oncogene occurs in about 13-15% of invasive breast cancer and triggers breast cancer cell proliferation, survival and metastatic progression. Around half of all breast cancers with HER2 overexpression co-express hormone receptors (HR) such as those for estrogen and progesterone. Aberrant signaling through HER2 and other members of the HER-family mediates endocrine-resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 therapies. These findings indicate that HER2 and ERα synergize to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER-family members in conjunction with a more efficient ERα blockade. Here, we demonstrate that carfilzomib and bortezomib stabilize the HER2-specific protein tyrosine phosphatase BDP1 leading to decreased HER2 autophosphorylation, reduced HER2 activity and subsequently attenuated activation of the PI3K/Akt-pathway, together with blockade of ERα expression. We further observed that proteasome inhibitors (PIs) reverse autophosphorylation and thereby inhibit the activity of constitutively active mutant HER2. We also demonstrate that PIs cause cell death in lapatinib and endocrine-resistant HER2+/ER+ breast cancer cells. These findings suggest that PIs might have the potential to improve the management of HER2+/ER+ breast cancer patients by efficiently disrupting the bi-directional HER2/ERα cross-talk.

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

    Directory of Open Access Journals (Sweden)

    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

  17. FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

    Science.gov (United States)

    Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

    2015-11-01

    On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ©2015 American Association for Cancer Research.

  18. Positive selection moments identify potential functional residues in human olfactory receptors

    Science.gov (United States)

    Singer, M. S.; Weisinger-Lewin, Y.; Lancet, D.; Shepherd, G. M.

    1996-01-01

    Correlated mutation analysis and molecular models of olfactory receptors have provided evidence that residues in the transmembrane domains form a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha-helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferentially affected by positive selection and are thus likely to interact with odor ligands. The results suggest that residue 622, which is commonly a serine or threonine, could form critical H-bonds. In some receptors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of these residues is further supported by site-directed mutagenesis in the beta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutagenesis.

  19. Genome-wide association studies identify four ER negative–specific breast cancer risk loci

    Science.gov (United States)

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van’t; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Silva, Isabel dos Santos; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; Van den Ouweland, Ans M W; Van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. PMID:23535733

  20. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

    Science.gov (United States)

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather S; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van't; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Dos Santos Silva, Isabel; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; van den Ouweland, Ans M W; van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-Gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter

    2013-04-01

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

  1. Dissecting the Biological Heterogeneity within Hormone Receptor Positive HER2 Negative Breast Cancer by Gene Expression Markers Identifies Indolent Tumors within Late Stage Disease

    Directory of Open Access Journals (Sweden)

    Jyothi S Prabhu

    2017-08-01

    Full Text Available Hormone receptor positive (HR+ breast cancers are a heterogeneous class with differential prognosis. Although more than half of Indian women present with advanced disease, many such patients do well. We have attempted identification of biologically indolent tumors within HR+HER2- tumors based on gene expression using histological grade as a guide to tumor aggression. 144 HR+HER2- tumors were divided into subclasses based on scores derived by using transcript levels of multiple genes representing survival, proliferation, and apoptotic pathways and compared to classification by Ki-67 labeling index (LI. Clinical characters and disease free survival were compared between the subclasses. The findings were independently validated in the METABRIC data set. Using the previously established estrogen receptor (ER down stream activity equation, 20% of the tumors with greater than 10% HR positivity by immunohistochemistry (IHC were still found to have inadequate ER function. A tumor aggression probability score was used to segregate the remainder of tumors into indolent (22% and aggressive (58% classes. Significant difference in disease specific survival was seen between the groups (P = .02. Aggression probability based subclassification had a higher hazard ratio and also independent prognostic value (P < .05. Independent validation of the gene panel in the METABRIC data set showed all 3 classes; indolent (24%, aggressive (68%, and insufficient ER signaling (7% with differential survival (P = .01. In agreement with other recent reports, biologically indolent tumors can be identified with small sets of gene panels and these tumors exist in a population with predominantly late stage disease.

  2. STIM1 positively regulates the Ca2+ release activity of the inositol 1,4,5-trisphosphate receptor in bovine aortic endothelial cells.

    Directory of Open Access Journals (Sweden)

    Éric Béliveau

    Full Text Available The endothelium is actively involved in many functions of the cardiovascular system, such as the modulation of arterial pressure and the maintenance of blood flow. These functions require a great versatility of the intracellular Ca2+ signaling that resides in the fact that different signals can be encoded by varying the frequency and the amplitude of the Ca2+ response. Cells use both extracellular and intracellular Ca2+ pools to modulate the intracellular Ca2+ concentration. In non-excitable cells, the inositol 1,4,5-trisphosphate receptor (IP3R, located on the endoplasmic reticulum (ER, is responsible for the release of Ca2+ from the intracellular store. The proteins STIM1 and STIM2 are also located on the ER and they are involved in the activation of a store-operated Ca2+ entry (SOCE. Due to their Ca2+ sensor property and their close proximity with IP3Rs on the ER, STIMs could modulate the activity of IP3R. In this study, we showed that STIM1 and STIM2 are expressed in bovine aortic endothelial cells and they both interact with IP3R. While STIM2 appears to play a minor role, STIM1 plays an important role in the regulation of agonist-induced Ca2+ mobilization in BAECs by a positive effect on both the SOCE and the IP3R-dependent Ca2+ release.

  3. STIM1 positively regulates the Ca2+ release activity of the inositol 1,4,5-trisphosphate receptor in bovine aortic endothelial cells.

    Science.gov (United States)

    Béliveau, Éric; Lessard, Vincent; Guillemette, Gaétan

    2014-01-01

    The endothelium is actively involved in many functions of the cardiovascular system, such as the modulation of arterial pressure and the maintenance of blood flow. These functions require a great versatility of the intracellular Ca2+ signaling that resides in the fact that different signals can be encoded by varying the frequency and the amplitude of the Ca2+ response. Cells use both extracellular and intracellular Ca2+ pools to modulate the intracellular Ca2+ concentration. In non-excitable cells, the inositol 1,4,5-trisphosphate receptor (IP3R), located on the endoplasmic reticulum (ER), is responsible for the release of Ca2+ from the intracellular store. The proteins STIM1 and STIM2 are also located on the ER and they are involved in the activation of a store-operated Ca2+ entry (SOCE). Due to their Ca2+ sensor property and their close proximity with IP3Rs on the ER, STIMs could modulate the activity of IP3R. In this study, we showed that STIM1 and STIM2 are expressed in bovine aortic endothelial cells and they both interact with IP3R. While STIM2 appears to play a minor role, STIM1 plays an important role in the regulation of agonist-induced Ca2+ mobilization in BAECs by a positive effect on both the SOCE and the IP3R-dependent Ca2+ release.

  4. Immunocytochemical study of estrogen receptor activation factor (E-RAF and the proteins that interact with nuclear estrogen receptor II (nER II in epithelial endometrial cells, in the presence and in the absence of estradiol

    Directory of Open Access Journals (Sweden)

    OM Echeverría

    2009-06-01

    Full Text Available The localization and abundance of the estrogen receptor activation factor (E-RAF and a small nuclear ribonucleoprotein (snRNP complex containing three proteins, p32, p55 and p60, which interact with the nuclear estrogen receptor II (nER II, have been studied in rat endometrial epithelial cells by means of immunofluorescence and high resolution quantitative immunocytochemistry. In the cytoplasm E-RAF is associated with the rough endoplasmic reticulum. In the nucleus it is mainly localized at the interchromatin space, and surrounding the clumps of compact or semi-condensed chromatin. Quantitative analyses show that the abundance of E-RAF in the nucleus increases after ovariectomy and decreases 3 minutes after estradiol administration. These results are in agreement with the currently available biochemical data. Double immunolocalizations demonstrate that p32, p55, p60 co-localize with other splicing-related protein. High resolution immunolocalization shows that p32, p55, p60 are associated with perichromatin fibrils (co-transcriptional splicing and with clusters of interchromatin granules (storage of splicing-related molecules. The nuclear abundance of the snRNP complex decreases with ovariectomy, increases within 3 minutes after estradiol administration and remains higher than that in ovariectomized animals for 27 minutes. These results strongly support the previous data on the role of nER-II in the regulation of mRNA transcription and its export from the nucleus to the cytoplasm.

  5. Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours

    Energy Technology Data Exchange (ETDEWEB)

    Essen, Martijn van; Krenning, Eric P.; Jong, Marion De; Valkema, Roelf; Kwekkeboom, Dik J. [Dept. of Nuclear Medicine, Erasmus MC, ' s Gravendijkwal 230, Rotterdam (Netherlands)

    2007-08-15

    Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various {sup 111}In, {sup 90}Y, or {sup 177}Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with {sup 111}Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like {sup 90}Y and {sup 177}Lu were developed. Reported anti-tumour effects of [{sup 90}Y-DOTA0,Tyr3]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [{sup 177}Lu-DOTA0,Tyr3]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [{sup 90}Y-DOTA0,Tyr3]octreotide and [{sup 177}Lu-DOTA0,Tyr3]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [{sup 177}Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non

  6. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation.

    Science.gov (United States)

    Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Milne, Roger L; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Alonso, M Rosario; Pita, Guillermo; Neuhausen, Susan L; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Haiman, Christopher A; Le Marchand, Loic; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Borresen-Dale, Anne-Lise; Zheng, Wei; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Devilee, Peter; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Koppert, Linetta B; Li, Jingmei; Shu, Xiao-Ou; Zheng, Ying; Cox, Angela; Cross, Simon S; Shah, Mitul; Rhenius, Valerie; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don M; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Schoemaker, Minouk J; Simard, Jacques; Pharoah, Paul D P; Kristensen, Vessela; Chenevix-Trench, Georgia; Easton, Douglas F; Dunning, Alison M; Edwards, Stacey L

    2016-10-06

    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). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Positive inotropy mediated via CGRP receptors in isolated human myocardial trabeculae

    DEFF Research Database (Denmark)

    Saetrum Opgaard, O; Hasbak, P; de Vries, R

    2000-01-01

    Isometric contractile force were studied on isolated human myocardial trabeculae that were paced at 1.0 Hz in tissue baths. Alpha calcitonin gene-related peptide (alpha-CGRP) had a potent positive inotropic effect in most trabeculae from both the right atrium and left ventricle, and this effect...... was partially antagonized by the CGRP(1) receptor antagonist alpha-CGRP-(8-37) (10(-6) M). Amylin and the CGRP(2) receptor agonist [Cys(acetylmethoxy)(2, 7)]CGRP had a positive inotropic effect in some trabeculae, whereas adrenomedullin had no inotropic effect. Using reverse transcriptase-polymerase chain...

  8. Sorting nexin 17 regulates ApoER2 recycling and reelin signaling.

    Science.gov (United States)

    Sotelo, Pablo; Farfán, Pamela; Benitez, María Luisa; Bu, Guojun; Marzolo, María-Paz

    2014-01-01

    ApoER2 is a member of the low density-lipoprotein receptor (LDL-R) family. As a receptor for reelin, ApoER2 participates in neuronal migration during development as well as synaptic plasticity and survival in the adult brain. A previous yeast two-hybrid screen showed that ApoER2 is a binding partner of sorting nexin 17 (SNX17) - a cytosolic adaptor protein that regulates the trafficking of several membrane proteins in the endosomal pathway, including LRP1, P-selectin and integrins. However, no further studies have been performed to investigate the role of SNX17 in ApoER2 trafficking and function. In this study, we present evidence based on GST pull-down and inmunoprecipitation assays that the cytoplasmic NPxY endocytosis motif of ApoER2 interacts with the FERM domain of SNX17. SNX17 stimulates ApoER2 recycling in different cell lines including neurons without affecting its endocytic rate and also facilitates the transport of ApoER2 from the early endosomes to the recycling endosomes. The reduction of SNX17 was associated with accumulation of an ApoER2 carboxy-terminal fragment (CTF). In addition, in SNX17 knockdown cells, constitutive ApoER2 degradation was not modified, whereas reelin-induced ApoER2 degradation was increased, implying that SNX17 is a regulator of the receptor's half-life. Finally, in SNX17 silenced hippocampal and cortical neurons, we underscored a positive role of this endosomal protein in the development of the dendritic tree and reelin signaling. Overall, these results establish the role of SNX17 in ApoER2 trafficking and function and aid in identifying new links between endocytic trafficking and receptor signaling.

  9. Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered

    Directory of Open Access Journals (Sweden)

    Yaw Awuni

    2015-03-01

    Full Text Available Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries.

  10. 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

  11. Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer

    DEFF Research Database (Denmark)

    Kodahl, Annette R; Lyng, Maria Bibi; Binder, Harald

    2014-01-01

    INTRODUCTION: There are currently no highly sensitive and specific minimally invasive biomarkers for detection of early-stage breast cancer. MicroRNAs (miRNAs) are present in the circulation and may be unique biomarkers for early diagnosis of human cancers. The aim of this study was to investigate......RNA signature to stratify samples from breast cancer patients and healthy controls was confirmed in the validation set (p = 0.012) with a corresponding AUC = 0.665 in the ROC-curve analysis. No association between miRNA expression and tumor grade, tumor size, menopausal- or lymph node status was observed....... The signature was also successfully validated in a previously published independent data set of circulating miRNAs in early-stage breast cancer (p = 0.024). CONCLUSIONS: We present herein a 9 miRNA signature capable of discriminating between ER-positive breast cancer and healthy controls. Using a specific...

  12. Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with postmenopausal estrogen receptor-positive advanced breast cancer: a subgroup analysis of the JBCRG-C06 Safari study.

    Science.gov (United States)

    Kawaguchi, Hidetoshi; Masuda, Norikazu; Nakayama, Takahiro; Aogi, Kenjiro; Anan, Keisei; Ito, Yoshinori; Ohtani, Shoichiro; Sato, Nobuaki; Saji, Shigehira; Takano, Toshimi; Tokunaga, Eriko; Nakamura, Seigo; Hasegawa, Yoshie; Hattori, Masaya; Fujisawa, Tomomi; Morita, Satoshi; Yamaguchi, Miki; Yamashita, Hiroko; Yamashita, Toshinari; Yamamoto, Yutaka; Yotsumoto, Daisuke; Toi, Masakazu; Ohno, Shinji

    2017-11-02

    The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this subgroup analysis was to further examine data from the Safari study, focusing on ER+ and human epidermal growth factor receptor-negative (HER2-) cases. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study, conducted in 1072 patients in Japan taking F500 for ER+ ABC. The subanalysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2-. Multivariate analysis showed that advanced age (≥65 years; p = 0.035), longer time (≥3 years) from AMBC ABC diagnosis to F500 use (p < 0.001), no prior chemotherapy (p < 0.001), and F500 treatment line (p < 0.001) were correlated with prolonged TTF (median 5.39 months). In ER+/HER2- patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

  13. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18.

    Science.gov (United States)

    Finn, Richard S; Crown, John P; Ettl, Johannes; Schmidt, Marcus; Bondarenko, Igor M; Lang, Istvan; Pinter, Tamas; Boer, Katalin; Patel, Ravindranath; Randolph, Sophia; Kim, Sindy T; Huang, Xin; Schnell, Patrick; Nadanaciva, Sashi; Bartlett, Cynthia Huang; Slamon, Dennis J

    2016-06-28

    Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319-0.748; one-sided p = 0.0004). Grade 3-4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3-4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3-4 neutropenia

  14. GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators.

    Science.gov (United States)

    Filip, Małgorzata; Frankowska, Małgorzata; Sadakierska-Chudy, Anna; Suder, Agata; Szumiec, Lukasz; Mierzejewski, Paweł; Bienkowski, Przemyslaw; Przegaliński, Edmund; Cryan, John F

    2015-01-01

    γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted. Copyright © 2014. Published by Elsevier Ltd.

  15. Computing highly correlated positions using mutual information and graph theory for G protein-coupled receptors.

    Directory of Open Access Journals (Sweden)

    Sarosh N Fatakia

    Full Text Available G protein-coupled receptors (GPCRs are a superfamily of seven transmembrane-spanning proteins involved in a wide array of physiological functions and are the most common targets of pharmaceuticals. This study aims to identify a cohort or clique of positions that share high mutual information. Using a multiple sequence alignment of the transmembrane (TM domains, we calculated the mutual information between all inter-TM pairs of aligned positions and ranked the pairs by mutual information. A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance. Positions with high degree (i.e. had significant mutual information with a large number of other positions were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs. Although the natural ligands of class C receptors bind to their extracellular N-terminal domains, the possibility of modulating their activity through ligands that bind to their helical bundle has been reported. Such positions were not found for class B GPCRs, in agreement with the observation that there are not known ligands that bind within their TM helical bundle. All identified key positions formed a clique within the MI graph of interest. For a subset of class A receptors we also considered the alignment of a portion of the second extracellular loop, and found that the two positions adjacent to the conserved Cys that bridges the loop with the TM3 qualified as key positions. Our algorithm may be useful for localizing topologically conserved regions in other protein families.

  16. Computing highly correlated positions using mutual information and graph theory for G protein-coupled receptors.

    Science.gov (United States)

    Fatakia, Sarosh N; Costanzi, Stefano; Chow, Carson C

    2009-01-01

    G protein-coupled receptors (GPCRs) are a superfamily of seven transmembrane-spanning proteins involved in a wide array of physiological functions and are the most common targets of pharmaceuticals. This study aims to identify a cohort or clique of positions that share high mutual information. Using a multiple sequence alignment of the transmembrane (TM) domains, we calculated the mutual information between all inter-TM pairs of aligned positions and ranked the pairs by mutual information. A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance. Positions with high degree (i.e. had significant mutual information with a large number of other positions) were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs. Although the natural ligands of class C receptors bind to their extracellular N-terminal domains, the possibility of modulating their activity through ligands that bind to their helical bundle has been reported. Such positions were not found for class B GPCRs, in agreement with the observation that there are not known ligands that bind within their TM helical bundle. All identified key positions formed a clique within the MI graph of interest. For a subset of class A receptors we also considered the alignment of a portion of the second extracellular loop, and found that the two positions adjacent to the conserved Cys that bridges the loop with the TM3 qualified as key positions. Our algorithm may be useful for localizing topologically conserved regions in other protein families.

  17. CCNA2 Is a Prognostic Biomarker for ER+ Breast Cancer and Tamoxifen Resistance

    OpenAIRE

    Gao, Tian; Han, Yong; Yu, Ling; Ao, Sheng; Li, Ziyu; Ji, Jiafu

    2014-01-01

    Identification of effective prognostic biomarkers and targets are of crucial importance to the management of estrogen receptor positive (ER+) breast cancer. CCNA2 (also known as CyclinA2) belongs to the highly conserved cyclin family and is significantly overexpressed in various cancer types. In this study, we demonstrated that CCNA2 had significant predictive power in distant metastasis free survival, disease free survival, recurrence free survival and overall survival of ER+ breast cancer p...

  18. Pattern of hormone receptors and human epidermal growth factor ...

    African Journals Online (AJOL)

    Introduction: Breast cancer is the most common cancer among women globally. With immunohistochemistry (IHC), breast cancer is classified into four groups based on IHC profile of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) expression, positive (+) and/or ...

  19. Multi-Domain Assembly of Nuclear Estrogen Receptors: Structural Insights into ER-Positive Breast Cancer Therapeutics

    Science.gov (United States)

    2013-04-01

    Bonvin. 2012 by the Biophysical Society 0006-3495/12/08/0837/9 $2.00dynamics (MD) simulations (10). Although the restriction to a short timescale...Specificity in protein-protein interactions: the structural basis for dual recognition in endonuclease colicin-immunity protein complexes. J. Mol. Biol. 301

  20. 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.

  1. Muscarinic receptor M4 positive allosteric modulators attenuate central effects of cocaine

    DEFF Research Database (Denmark)

    Dall, Camilla; Weikop, Pia; Dencker, Ditte

    2017-01-01

    BACKGROUND: Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that spe......BACKGROUND: Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis....... As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference. CONCLUSIONS......: These findings further support the notion that M4 receptors are promising targets for the treatment of cocaine addiction, by showing that results can be replicated using distinct ligands, and that in addition to blocking reinforcing effects of cocaine relevant to ongoing drug taking, M4 positive allosteric...

  2. Palbociclib for the Treatment of Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

    Science.gov (United States)

    Morikawa, Aki; Henry, N Lynn

    2015-08-15

    Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 that acts by reducing phosphorylation of the tumor suppressor gene retinoblastoma. When added to the aromatase inhibitor letrozole in a randomized phase II trial for first-line therapy of estrogen receptor-positive, HER2-negative metastatic breast cancer, palbociclib significantly increased progression-free survival compared with letrozole alone [palbociclib + letrozole: 20.2 months; 95% confidence interval (CI), 13.8-27.5; letrozole: 10.2 months; 95% CI, 5.7-12.6; HR, 0.49; 95% CI, 0.32-0.75; P = 0.0004]. On the basis of these results, the drug was recently granted accelerated approval by the FDA, and confirmatory studies are ongoing. Because this drug has a rational target in an oncologic pathway, concurrent biomarker development is of interest. In breast cancer, the most useful predictive biomarkers identified thus far are estrogen receptor and HER2 receptor status, although additional studies are ongoing. In this article, we review the development of palbociclib and its use in treatment of hormone receptor-positive metastatic breast cancer in the context of other FDA-approved agents in this setting. ©2015 American Association for Cancer Research.

  3. Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice

    OpenAIRE

    Li, Xia; Risbrough, Victoria B.; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M. G.; Roberts, Amanda J; Markou, Athina

    2013-01-01

    γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicy...

  4. Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.

    Directory of Open Access Journals (Sweden)

    Sylvie Bretin

    Full Text Available S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA receptors (AMPA-PAM. S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants (EC50 between 2.5-5.4 μM, except a higher EC50 value for GluA4 flop (0.7 μM and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 μM decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 μM in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 μM was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 μM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in

  5. Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.

    Science.gov (United States)

    Prat, Aleix; Cheang, Maggie Chon U; Martín, Miguel; Parker, Joel S; Carrasco, Eva; Caballero, Rosalía; Tyldesley, Scott; Gelmon, Karen; Bernard, Philip S; Nielsen, Torsten O; Perou, Charles M

    2013-01-10

    Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14

  6. Electrophysiological findings in patients with low density lipoprotein receptor related protein 4 positive myasthenia gravis.

    Science.gov (United States)

    Nikolic, A V; Bojic, S D; Rakocevic Stojanovic, V M; Basta, I Z; Lavrnic, D V

    2016-11-01

    The aim was to determine the electrophysiological profile of our cohort of low density lipoprotein receptor related protein 4 (LRP4) positive myasthenia gravis (MG) patients. A repetitive nerve stimulation (RNS) test and jitter analysis using a concentric needle electrode were performed in 17 LRP4 positive MG patients. The results were compared to 31 muscle-specific tyrosine kinase (MuSK) positive and 28 acetylcholine receptor (AChR) positive MG patients. The RNS test was negative in almost all patients belonging to the LRP4/seronegative and LRP4/MuSK groups. It was positive most frequently in the AChR MG patients, especially those without anti-LRP4 antibodies. The presence of anti-LRP4 antibodies was connected to lower decrement values, whilst the independent presence of anti-AChR or anti-MuSK antibodies was connected to higher decrement values. Lowest jitter was recorded in patients with LRP4/seronegative MG. The highest percentage of pathological jitter analysis test results was present in MuSK and AChR MG patients. The isolate presence of anti-LRP4 antibodies did not influence the mean consecutive difference values, whilst mean consecutive difference values were higher in the presence of anti-AChR or anti-MuSK antibodies. Low density lipoprotein receptor related protein 4 positive patients make a distinct MG subgroup with rarely detected pathological electrophysiological test results. The lack of influence of anti-LRP4 antibodies on the different electrophysiological parameters brings into question the pathogenic role of anti-LRP4 antibodies in MG. © 2016 EAN.

  7. Muscarinic receptor M4 positive allosteric modulators attenuate central effects of cocaine.

    Science.gov (United States)

    Dall, Camilla; Weikop, Pia; Dencker, Ditte; Molander, Anna C; Wörtwein, Gitta; Conn, P Jeffrey; Fink-Jensen, Anders; Thomsen, Morgane

    2017-07-01

    Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M4 receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking. We tested the M4-selective positive allosteric modulators VU0152100 and VU0467154 in a drug discrimination assay and a conditioned place preference assay, including extinction and reinstatement of place preference. Specificity of the cocaine discrimination effect was verified using knockout mice lacking either M1 or M4 receptors (M1-/-, M4-/-). We also replicated previous findings in cocaine-induced locomotor hyperactivity and striatal dopamine microdialysis assays. VU0152100 attenuated the discriminative stimulus effect of cocaine in wild-type mice and M1-/- mice, but not in M4-/- mice, without affecting rates of responding. As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference. These findings further support the notion that M4 receptors are promising targets for the treatment of cocaine addiction, by showing that results can be replicated using distinct ligands, and that in addition to blocking reinforcing effects of cocaine relevant to ongoing drug taking, M4 positive allosteric modulators can also attenuate subjective and conditioned effects relevant to relapse. Copyright © 2017. Published by Elsevier B.V.

  8. PAC₁ receptors mediate positive chronotropic responses to PACAP-27 and VIP in isolated mouse atria.

    Science.gov (United States)

    Hoover, Donald B; Girard, Beatrice M; Hoover, Jeffrey L; Parsons, Rodney L

    2013-08-05

    PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC₁, VPAC₁, and VPAC₂ receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC₁ being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC₁ agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a logEC₅₀=-9.08 ± 0.15 M (n=7) and a maximum of 96.3 ± 5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC₁ receptors mediate positive chronotropic responses to PACAP-27 and VIP. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. A Radio-genomics Approach for Identifying High Risk Estrogen Receptor-positive Breast Cancers on DCE-MRI: Preliminary Results in Predicting OncotypeDX Risk Scores

    Science.gov (United States)

    Wan, Tao; Bloch, B. Nicolas; Plecha, Donna; Thompson, Cheryi L.; Gilmore, Hannah; Jaffe, Carl; Harris, Lyndsay; Madabhushi, Anant

    2016-02-01

    To identify computer extracted imaging features for estrogen receptor (ER)-positive breast cancers on dynamic contrast en-hanced (DCE)-MRI that are correlated with the low and high OncotypeDX risk categories. We collected 96 ER-positivebreast lesions with low (30, N = 41) OncotypeDX recurrence scores. Each lesion was quantitatively charac-terize via 6 shape features, 3 pharmacokinetics, 4 enhancement kinetics, 4 intensity kinetics, 148 textural kinetics, 5 dynamic histogram of oriented gradient (DHoG), and 6 dynamic local binary pattern (DLBP) features. The extracted features were evaluated by a linear discriminant analysis (LDA) classifier in terms of their ability to distinguish low and high OncotypeDX risk categories. Classification performance was evaluated by area under the receiver operator characteristic curve (Az). The DHoG and DLBP achieved Az values of 0.84 and 0.80, respectively. The 6 top features identified via feature selection were subsequently combined with the LDA classifier to yield an Az of 0.87. The correlation analysis showed that DHoG (ρ = 0.85, P cancers.

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

    Directory of Open Access Journals (Sweden)

    Gray Joe

    2008-11-01

    Full Text Available Abstract Background 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. Methods 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. Results A 14-gene signature was found to be significantly associated (p Conclusion The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  12. Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20-44 years of age.

    Science.gov (United States)

    Li, Christopher I; Beaber, Elisabeth F; Tang, Mei-Tzu Chen; Porter, Peggy L; Daling, Janet R; Malone, Kathleen E

    2013-01-01

    Aspects of reproductive history are among the most well-established breast cancer risk factors. However, relatively little is known about how they influence risk of different molecular subtypes of breast cancer, particularly among younger women. Using data from a population-based case-control study of women 20-44 years of age, we assessed the relationships between various reproductive factors and risk of estrogen receptor positive (ER+), triple-negative, and HER2-overexpressing breast cancers. Detailed reproductive histories were obtained through structured interviewer administered in-person questionnaires. Reproductive histories among control women (n = 941) were compared to those of ER+ cases (n = 781), triple-negative cases (n = 180), and HER2-overexpressing cases (n = 60) using polytomous logistic regression. Age at menarche, parity, and number of full-term pregnancies were similarly associated with risk of all three breast cancer subtypes. In contrast, age at first live birth, the interval between age at menarche and age at first birth, and breastfeeding were inversely associated with risk of triple-negative breast cancer (P values for trend 0.002, 0.006 and 0.018, respectively), but were not associated with risk of ER+ or HER2-overexpressing cancers. A strong inverse association between breastfeeding and risk of triple-negative breast cancer has now been consistently observed across numerous studies, and at present it is the most well-established protective factor for this aggressive and lethal form of breast cancer. Further studies clarifying the biological mechanisms underlying this relationship and confirming our results with respect to age at first birth and the interval between age at menarche and age at first birth are needed.

  13. Phospho-aspirin-2 (MDC-22 inhibits estrogen receptor positive breast cancer growth both in vitro and in vivo by a redox-dependent effect.

    Directory of Open Access Journals (Sweden)

    Liqun Huang

    Full Text Available Phospho-aspirin (PA-2 is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+ breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, p<0.01. PA-2 triggered the activation of p53-dependent apoptosis via two distinct mechanisms: 1 acetylation of p53 (at K373, which disrupts its interaction with its transcription repressor MDM2, and 2 translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨ(m. Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.

  14. Phospho-aspirin-2 (MDC-22) inhibits estrogen receptor positive breast cancer growth both in vitro and in vivo by a redox-dependent effect.

    Science.gov (United States)

    Huang, Liqun; Wong, Chi C; Cheng, Ka W; Rigas, Basil

    2014-01-01

    Phospho-aspirin (PA-2) is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+) breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, pmechanisms: 1) acetylation of p53 (at K373), which disrupts its interaction with its transcription repressor MDM2, and 2) translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨ(m)). Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.

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

    Energy Technology Data Exchange (ETDEWEB)

    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, 17..cap alpha..- bromovinylestradiol, BrVE/sub 2/, were labeled with the Auger electron emitting nuclide bromine-80m, prepared by the (p,n) reaction with /sup 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/sub 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/sub 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.

  16. Progress in the developement of positive allosteric modulators of the metabotropic glutamate receptor 2.

    Science.gov (United States)

    Trabanco, A A; Cid, J M; Lavreysen, H; Macdonald, G J; Tresadern, G

    2011-01-01

    The metabotropic glutamate type 2 (mGlu2) receptor is a G-protein coupled receptor (GPCR) expressed on presynaptic nerve terminals where it negatively modulates glutamate and GABA release. Mixed mGlu2/mGlu3 orthosteric agonists such as LY354740 have shown activity in a range of preclinical animal models of anxiety and schizophrenia. Clinical work with LY354740 demonstrated activity in a CO(2) inhalation study suggesting application in the treatment of anxiety related disorders. Subsequently, a related prodrug LY2140023 demonstrated improvements in positive and negative symptoms in patients suffering from schizophrenia. These molecules exhibit combined mGlu2/mGlu3 activity although there is evidence from knock-out studies that preclinical anti-psychotic effects may be mediated via the mGlu2 receptor. An alternative avenue for modulating GPCRs is to act via allosteric mechanisms, binding at a different site from the orthosteric agonist. Since the first discovery of mGlu2 positive allosteric modulators (PAMs) such as 2,2,2-TEMPS and BINA, multiple families of mGlu2 modulators have been reported and several have entered into clinical development. This review focuses on recent advances in the development of novel mGlu2 PAMs by analysis of compounds disclosed in research articles and patent literature between 2007 and 2010.

  17. Genetic Imaging of the Association of Oxytocin Receptor Gene (OXTR Polymorphisms with Positive Maternal Parenting

    Directory of Open Access Journals (Sweden)

    Kalina J. Michalska

    2014-02-01

    Full Text Available Background: Well-validated models of maternal behavior in small-brain mammals posit a central role of oxytocin in parenting, by reducing stress and enhancing the reward value of social interactions with offspring. In contrast, human studies are only beginning to gain insights into how oxytocin modulates maternal behavior and affiliation. Methods: To explore associations between oxytocin receptor genes and maternal parenting behavior in humans, we conducted a genetic imaging study of women selected to exhibit a wide range of observed parenting when their children were 4-6 years old. Results: In response to child stimuli during functional magnetic resonance imaging, hemodynamic responses in brain regions that mediate affect, reward, and social behavior were significantly correlated with observed positive parenting. Furthermore, single nucleotide polymorphisms (rs53576 and rs1042778 in the gene encoding the oxytocin receptor were significantly associated with both positive parenting and hemodynamic responses to child stimuli in orbitofrontal cortex, anterior cingulate cortex and hippocampus. Conclusions: These findings contribute to the emerging literature on the role of oxytocin in human social behavior and support the feasibility of tracing biological pathways from genes to neural regions to positive maternal parenting behaviors in humans using genetic imaging methods.

  18. The TM2 6′ Position of GABAA Receptors Mediates Alcohol Inhibition

    Science.gov (United States)

    Howard, Rebecca J.; Trudell, James R.; Harris, R. Adron

    2012-01-01

    Ionotropic GABAA receptors (GABAARs), which mediate inhibitory neurotransmission in the central nervous system, are implicated in the behavioral effects of alcohol and alcoholism. Site-directed mutagenesis studies support the presence of discrete molecular sites involved in alcohol enhancement and, more recently, inhibition of GABAARs. We used Xenopus laevis oocytes to investigate the 6′ position in the second transmembrane region of GABAARs as a site influencing alcohol inhibition. We asked whether modification of the 6′ position by substitution with larger residues or methanethiol labeling [using methyl methanethiosulfonate (MMTS)] of a substituted cysteine, reduced GABA action and/or blocked further inhibition by alcohols. Labeling of the 6′ position in either α2 or β2 subunits reduced responses to GABA. In addition, methanol and ethanol potentiation increased after MMTS labeling or substitution with tryptophan or methionine, consistent with elimination of an inhibitory site for these alcohols. Specific alcohols, but not the anesthetic etomidate, competed with MMTS labeling at the 6′ position. We verified a role for the 6′ position in previously tested α2β2 as well as more physiologically relevant α2β2γ2s GABAARs. Finally, we built a novel molecular model based on the invertebrate glutamate-gated chloride channel receptor, a GABAAR homolog, revealing that the 6′ position residue faces the channel pore, and modification of this residue alters volume and polarity of the pore-facing cavity in this region. These results indicate that the 6′ positions in both α2 and β2 GABAAR subunits mediate inhibition by short-chain alcohols, which is consistent with the presence of multiple counteracting sites of action for alcohols on ligand-gated ion channels. PMID:22072732

  19. 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.)

  20. Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment.

    Science.gov (United States)

    Bell, T; Crown, J P; Lang, I; Bhattacharyya, H; Zanotti, G; Randolph, S; Kim, S; Huang, X; Huang Bartlett, C; Finn, R S; Slamon, D

    2016-05-01

    Background Palbociclib is a recently approved drug for use in combination with letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This report assesses the impact of palbociclib in combination with letrozole versus letrozole alone on patient-reported outcomes of pain. Methods Palbociclib was evaluated in an open-label, randomized, phase II study (PALOMA-1/TRIO-18) among postmenopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic treatment for their advanced disease. Patients received continuous oral letrozole 2.5 mg daily alone or the same letrozole dose and schedule plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over repeated 28-day cycles. The primary study endpoint was investigator-assessed progression-free survival in the intent-to-treat population, and these results have recently been published (Finn et al., Lancet Oncol 2015;16:25-35). One of the key secondary endpoints was the evaluation of pain, as measured using the Brief Pain Inventory (BPI) patient-reported outcome tool. The BPI was administered at baseline and on day 1 of every cycle thereafter until disease progression and/or treatment discontinuation. Clinical trial registration This study is registered with ClinicalTrials.gov (NCT00721409). Results There were no statistically significant differences in Pain Severity or Pain Interference scores of the BPI between the two treatment groups for the overall population or among those with any bone disease at baseline. A limitation of the study is that results were not adjusted for the concomitant use of opioids or other medications used to control pain. Conclusions The addition of palbociclib to letrozole was associated with increased efficacy without negatively impacting pain severity or pain interference with daily activities.

  1. Risk of mortality of node-negative, ER/PR/HER2 breast cancer subtypes in T1, T2, and T3 tumors.

    Science.gov (United States)

    Parise, Carol A; Caggiano, Vincent

    2017-10-01

    The purpose of this study was to assess differences in breast cancer-specific mortality within tumors of the same size when breast cancer was defined using the three tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We identified 104,499 cases of node-negative primary female invasive breast cancer from the California Cancer Registry. Tumor size was categorized as T1a, T1b, T1c, T2, and T3. Breast cancer was defined using ER, PR, and HER2. Kaplan-Meier Survival analysis was conducted and Cox Regression was used to compute the adjusted risk of mortality for the ER+/PR+/HER2+, ER-/PR-/HER2- (TNBC), and ER-/PR-/HER2+ (HER2-overexpressing) subtypes when compared with the ER+/PR+/HER2-. Separate models were computed for each tumor size. Unadjusted survival analysis showed that for all tumor sizes, the ER+/PR+ subtypes regardless of HER status have better breast cancer-specific survival than ER-/PR- subtypes. Subtype was not an important factor for risk of mortality for T1a tumors. The ER+/PR+/HER2+ subtype was only a risk for mortality in T1b tumors that were unadjusted for treatment. For all other tumor sizes, the ER+/PR+/HER2+ had the same mortality as the ER+/PR+/HER2- subtype regardless of adjustment for treatment. The HER2-overexpressing subtype had a higher risk of mortality than the ER+/PR+/HER2- subtype except for T1b tumors that were adjusted for treatment. For all tumor sizes, the TNBC had higher hazard ratios than all other subtypes. T1a tumors have the same risk of mortality regardless of ER/PR/HER2 subtype, and ER and PR negativity plays a stronger role in survival than HER2 positivity for tumors of all size.

  2. A phase 1 trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer

    Science.gov (United States)

    Ma, Cynthia X.; Luo, Jingqin; Naughton, Michael; Ademuyiwa, Foluso; Suresh, Rama; Griffith, Malachi; Griffith, Obi L.; Skidmore, Zachary L.; Spies, Nicholas C.; Ramu, Avinash; Trani, Lee; Pluard, Timothy; Nagaraj, Gayathri; Thomas, Shana; Guo, Zhanfang; Hoog, Jeremy; Han, Jing; Mardis, Elaine; Lockhart, Craig; Ellis, Matthew J.

    2016-01-01

    Purpose This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive breast cancer (ER+BC). Experimental Design Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts evaluated intermittent (5 of 7 day dosing) and continuous buparlisib (100mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in Phase IB and Cohort C. Results Thirty one patients were enrolled. MTD was defined as buparlisib 100mg daily plus fulvestrant. Common adverse events (AEs) included fatigue (38.7 %), transaminases elevation (35.5 %), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared to intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI 40.7–74.5%). Response was not associated with PIK3CA mutation or treatment cohort, however loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was commoner in resistant cases and mutations in AKT1 and ESR1 did not exclude treatment response. Conclusion Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER+BC. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features. PMID:26563128

  3. Prognostic effect of estrogen receptor status across age in primary breast cancer

    DEFF Research Database (Denmark)

    Bentzon, Niels; Düring, Maria; Rasmussen, Birgitte Bruun

    2008-01-01

    Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age...... and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive...... unchanged in patients who did not receive adjuvant systemic therapy (n = 6,272). Thus, positive ER status does not confer a negative impact on survival in young women as has been previously reported. The inferior prognosis for ER negative patients during the first 5 years after diagnosis changes...

  4. Updates on the treatment of human epidermal growth factor receptor type 2-positive breast cancer.

    Science.gov (United States)

    Kim, Miriam; Agarwal, Surbhi; Tripathy, Debu

    2014-02-01

    To review the most recent developments in the treatment of human epidermal growth factor receptor type 2 (HER2)-positive breast cancer with novel HER2-targeting agents and combinations that have significantly improved clinical outcomes. Since the approval of trastuzumab 15 years ago, the natural history of HER2-positive breast cancer has been altered with improvements in survival for both early and advanced disease with the addition of this agent to standard chemotherapy. The HER2 receptor pathway drives breast cancer growth and aggressiveness, and HER2-targeted agents can improve survival in early and advanced disease. In the advanced setting, two new drugs have been approved since 2012, pertuzumab and ado-trastuzumab emtansine (T-DM1), both of which improve survival without any reciprocal increase in toxicity. However, resistance almost always ensues, pointing to the need to understand the driving mechanisms and to biomarkers that will help individualize therapy and point to newer signal transduction and other modulators. HER2-positive breast cancer represents a distinct subtype with more aggressive clinical characteristics. HER2-targeted therapies, usually in combination with chemotherapy, are the standard of care, improving the cure rate in early-stage breast cancer and lengthening survival in the advanced setting.

  5. Clinical correlations of steroid receptors and male breast cancer.

    Science.gov (United States)

    Everson, R B; Lippman, M E; Thompson, E B; McGuire, W L; Wittliff, J L; De Sombre, E R; Jensen, E V; Singhakowinta, A; Brooks, S C; Neifeld, J P

    1980-04-01

    Estrogen receptors (ER) were present in tumor specimens from 29 of 34 cases of male breast cancer. There was a significant negative correlation of ER concentration with age. The quantity of ER tended to correlate directly with progesterone receptor levels, disease-free interval, and response duration among responders, but not to a statistically significant extent. In 13 patients for whom response data were available, no significant correlation was observed between ER levels and either frequency or duration of orchiectomy response. Among the six patients with tumor ER levels of less than 30 fmol per mg of protein, however, only two brief responses to orchiectomy occurred that were of little clinical benefit, while three of seven patients with higher ER responded more favorably. Thus, although this suggests that a relationship between low ER and unfavorable orchiectomy response may emerge as more patients are studied, currently available data do not justify basing therapeutic intervention on ER status of a biopsy in a manner analogous to that used for female breast cancer. Nine of 14 male breast cancer patients had positive progesterone receptor assays and several had androgen or glucocorticoid receptors. Tissue from only three of ten men with gynecomastia had measurable ER, and these were limited to the 4S component on sucrose gradients.

  6. Trastuzumab Emtansine in Treating Older Patients With Human Epidermal Growth Factor Receptor 2-Positive Stage I-III Breast Cancer

    Science.gov (United States)

    2018-02-01

    Estrogen Receptor Status; HER2 Positive Breast Carcinoma; Progesterone Receptor Status; Stage I Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  7. Signatures of positive selection in Toll-like receptor (TLR genes in mammals

    Directory of Open Access Journals (Sweden)

    Areal Helena

    2011-12-01

    Full Text Available Abstract Background Toll-like receptors (TLRs are a major class of pattern recognition receptors (PRRs expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs. TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9 and non-viral (TLR1-6, 10, were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. Results By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC ranged between 2-26 codons (0.25%-2.65% with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%, followed by the viral TLR8 (2.50%. The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. Conclusions Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be

  8. Neoadjuvant chemotherapy in ER+ HER2- breast cancer: response prediction based on immunohistochemical and molecular characteristics

    NARCIS (Netherlands)

    Lips, E. H.; Mulder, L.; de Ronde, J. J.; Mandjes, I. A. M.; Vincent, A.; Vrancken Peeters, M. T. F. D.; Nederlof, P. M.; Wesseling, J.; Rodenhuis, S.

    2012-01-01

    A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy in estrogen receptor-positive (ER+) HER2-negative (HER2-) tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be spared

  9. 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

    Science.gov (United States)

    Warren, Helen; Dudbridge, Frank; Fletcher, Olivia; Orr, Nick; Johnson, Nichola; Hopper, John L.; Apicella, Carmel; Southey, Melissa C.; Mahmoodi, Maryam; Schmidt, Marjanka K.; Broeks, Annegien; Cornelissen, Sten; Braaf, Linda M.; Muir, Kenneth R.; Lophatananon, Artitaya; Chaiwerawattana, Arkom; Wiangnon, Surapon; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Schulz-Wendtland, Ruediger; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Mulot, Claire; Bojesen, Stig E; Nielsen, Sune F.; Flyger, Henrik; Nordestgaard, Børge G; Milne, Roger L.; Benítez, Javier; Arias-Pérez, José-Ignacio; Zamora, M. Pilar; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Langheinz, Anne; Meindl, Alfons; Golatta, Michael; Bartram, Claus R.; Schmutzler, Rita K.; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Dörk, Thilo; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia; Antonenkova, Natalia; Rogov, Yuriy; Bermisheva, Marina; Prokofyeva, Darya; Zinnatullina, Guzel; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Kataja, Vesa; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Lambrechts, Diether; Smeets, Ann; Paridaens, Robert; Weltens, Caroline; Flesch-Janys, Dieter; Buck, Katharina; Behrens, Sabine; Peterlongo, Paolo; Bernard, Loris; Manoukian, Siranoush; Radice, Paolo; Couch, Fergus J.; Vachon, Celine; Wang, Xianshu; Olson, Janet; Giles, Graham; Baglietto, Laura; McLean, Cariona A.; Severi, Gianluca; John, Esther M.; Miron, Alexander; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Mulligan, Anna Marie; Weerasooriya, Nayana; Devilee, Peter; Tollenaar, Robert A.E.M.; Martens, John W.M.; Seynaeve, Caroline M.; Hooning, Maartje J.; Hollestelle, Antoinette; Jager, Agnes; Tilanus-Linthorst, Madeleine M.A.; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Cox, Angela; Cross, Simon S.; Brock, Ian W.; Reed, Malcolm W.R.; Pharoah, Paul; Blows, Fiona M.; Dunning, Alison M.; Ghoussaini, Maya; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk; Easton, Douglas F.; Humphreys, Manjeet; Wang, Qin; Peto, Julian; dos-Santos-Silva, Isabel

    2013-01-01

    Background Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10–29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10–143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10–22) but less strongly, if at all, with ER-negative (ER–) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10–6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact The findings further support the view that genetic susceptibility varies according to tumor subtype. PMID:22859399

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Locoregional Recurrence Risk in Breast Cancer Patients with Estrogen Receptor Positive Tumors and Residual Nodal Disease following Neoadjuvant Chemotherapy and Mastectomy without Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Shravan Kandula

    2015-01-01

    Full Text Available Among breast cancer patients treated with neoadjuvant chemotherapy (NAC and mastectomy, locoregional recurrence (LRR rates are unclear in women with ER+ tumors treated with adjuvant endocrine therapy without postmastectomy radiation (PMRT. To determine if PMRT is needed in these patients, we compared LRR rates of patients with ER+ tumors (treated with adjuvant endocrine therapy with women who have non-ER+ tumors. 85 consecutive breast cancer patients (87 breast tumors treated with NAC and mastectomy without PMRT were reviewed. Patients were divided by residual nodal disease (ypN status (ypN+ versus ypN0 and then stratified by receptor subtype. Among ypN+ patients (n=35, five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 5%, 33%, and 37%, respectively (p=0.02. Among ypN+/ER+ patients, lymphovascular invasion and grade three disease increased the five-year LRR risk to 13% and 11%, respectively. Among ypN0 patients (n=52, five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 7%, 22%, and 6%, respectively (p=0.71. In women with ER+ tumors and residual nodal disease, endocrine therapy may be sufficient adjuvant treatment, except in patients with lymphovascular invasion or grade three tumors where PMRT may still be indicated.

  12. ER and PR signaling nodes during mammary gland development.

    Science.gov (United States)

    Tanos, Tamara; Rojo, Lucia; Echeverria, Pablo; Brisken, Cathrin

    2012-07-19

    The ovarian hormones estrogen and progesterone orchestrate postnatal mammary gland development and are implicated in breast cancer. Most of our understanding of the molecular mechanisms of estrogen receptor (ER) and progesterone receptor (PR) signaling stems from in vitro studies with hormone receptor-positive cell lines. They have shown that ER and PR regulate gene transcription either by binding to DNA response elements directly or via other transcription factors and recruiting co-regulators. In addition they cross-talk with other signaling pathways through nongenomic mechanisms. Mouse genetics combined with tissue recombination techniques have provided insights about the action of these two hormones in vivo. It has emerged that hormones act on a subset of mammary epithelial cells and relegate biological functions to paracrine factors. With regards to hormonal signaling in breast carcinomas, global gene expression analyses have led to the identification of gene expression signatures that are characteristic of ERα-positive tumors that have stipulated functional studies of hitherto poorly understood transcription factors. Here, we highlight what has been learned about ER and PR signaling nodes in these different systems and attempt to lay out in which way the insights may converge.

  13. 5-(N, N-Hexamethylene) amiloride is a GABA-A ρ1 receptor positive allosteric modulator.

    Science.gov (United States)

    Snell, Heather D; Gonzales, Eric B

    2016-11-01

    Guanidine compounds act as ion channel modulators. In the case of Cys-loop receptors, the guanidine compound amiloride antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors. However, amiloride exhibits characteristics consistent with a positive allosteric modulator for the human GABA-A (hGABA-A) ρ1 receptor. Site-directed mutagenesis revealed that the positive allosteric modulation was influenced by the GABA-A ρ1 second transmembrane domain 15' position, a site implicated in ligand allosteric modulation of Cys-loop receptors. There are a variety of amiloride derivatives that provide opportunities to assess the significance of amiloride functional groups (e.g., the guanidine group, the pyrazine ring, etc.) in the modulation of the GABA-A ρ1 receptor activity. We utilized 3 amiloride derivatives (benzamil, phenamil, and 5-(N, N-Hexamethylene) amiloride) to assess the contribution of these groups toward the potentiation of the GABA-A ρ1 receptor. Benzamil and phenamil failed to potentiate on the wild type GABA-A ρ1 GABA-mediated current while HMA demonstrated efficacy only at the highest concentration studied. The hGABA-A ρ1 (I15'N) mutant receptor activity was potentiated by lower HMA concentrations compared to the wild type receptor. Our findings suggest that an exposed guanidine group on amiloride and amiloride derivatives is critical for modulating the GABA-A ρ1 receptor. The present study provides a conceptual framework for predicting which amiloride derivatives will demonstrate positive allosteric modulation of the GABA-A ρ1 receptor.

  14. 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.

  15. Reelin-dependent ApoER2 downregulation uncouples newborn neurons from progenitor cells

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    F. Javier Pérez-Martínez

    2012-10-01

    Reelin and its receptor machinery are well known to be required for the migration and positioning of neocortical projection neurons. More recently, reelin has been shown both necessary and sufficient to determine the rate of neocortical neurogenesis. The molecular links underlying its seemingly distinct proliferative and post-proliferative functions remain unknown. Here we reveal an enriched expression of functional reelin receptors, largely of Apolipoprotein E Receptor 2 (ApoER2, in radial glia basal processes and intermediate progenitor cells during mid/late cortical development. In vivo, ApoER2 overexpression inhibits neuronal migration. In contrast, precluding excessive levels of ApoER2 in reelin-deficient cortices, by either ApoER2 knock-down or the transgenic expression of reelin in neural progenitor cells, improves neuronal migration and positioning. Our study provides groundwork for the highly orchestrated clearance of neocortical neurons from their birth site, suggesting that a reelin-dependent ApoER2 downregulation mechanism uncouples newborn neurons from progenitor cells, thereby enabling neurons to migrate.

  16. Steroid hormone receptor expression in ovarian cancer: progesterone receptor B as prognostic marker for patient survival

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    Lenhard Miriam

    2012-11-01

    Full Text Available Abstract Background There is partially conflicting evidence on the influence of the steroid hormones estrogen (E and progesterone (P on the development of ovarian cancer (OC. The aim of this study was to assess the expression of the receptor isoforms ER-α/-β and PR-A/-B in OC tissue and to analyze its impact on clinical and pathological features and patient outcome. Methods 155 OC patients were included who had been diagnosed and treated between 1990 and 2002. Patient characteristics, histology and follow-up data were available. ER-α/-β and PR-A/-B expression were determined by immunohistochemistry. Results OC tissue was positive for ER-α/-β in 31.4% and 60.1% and PR-A/-B in 36.2% and 33.8%, respectively. We identified significant differences in ER-β expression related to the histological subtype (p=0.041, stage (p=0.002 and grade (p=0.011 as well as PR-A and tumor stage (p=0.03. Interestingly, median receptor expression for ER-α and PR-A/-B was significantly higher in G1 vs. G2 OC. Kaplan Meier analysis revealed a good prognosis for ERpositive (p=0.039 and PR-B positive (p Conclusion ER-α/-β and PR-A/-B are frequently expressed in OC with a certain variability relating to histological subtype, grade and stage. Univariate analysis indicated a favorable outcome for ERpositive and PR-B positive OC, while multivariate analysis showed PR-B to be the only independent prognostic marker for patient survival. In conclusion, ER and PR receptors may be useful targets for a more individualized OC therapy.

  17. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

    NARCIS (Netherlands)

    Milne, Roger L.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary K; Bolla, Manjeet K.; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M.; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B.; Amos, Christopher I; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L.; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B.; Barrdahl, Myrto; Barnes, Daniel R; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W.; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves Jean; Blazer, Kathleen R.; Blok, Marinus J.; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V.; Bojesen, Anders; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela R; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S.; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A.; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G.; Cross, Simon S.; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M.; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A.; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D.; Ganz, Patricia A; Gapstur, Susan M.; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M.; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne Marie; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H.; Alnæs, Grethe I Grenaker; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V. O.; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M.; Healey, Catherine S.; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane S.; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley V.; Hogervorst, Frans Bl; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Bob; Hopper, John L.; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M.; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J.; Kets, Carolien M.; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A.; Konstantopoulou, Irene; Kosma, Veli Matti; Kristensen, Vessela N.; Kruse, Torben A.; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; So, Wing Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael J.; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E.; Manoukian, Siranoush; Manson, Joann E.; Margolin, Sara; Martens, John W. M.; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; Mclean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F.; Nordestgaard, Børge G.; Norman, Aaron; Nussbaum, Robert L.; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Olswold, Curtis; Ong, Kai Ren; Oosterwijk, Jan C.; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose Ignacio Arias; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M.; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E.; Prentice, Ross L.; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C.; Romero, Atocha; Romm, Jane; Rookus, Matti A.; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Daniel F.; Schoemaker, Minouk J.; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J.; Shu, Xiao Ou; Side, Lucy E.; Singer, Christian F.; Sohn, Christof; Southey, Melissa C.; Spinelli, John J; Spurdle, Amanda B.; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald M.; Sutter, Christian; Swerdlow, Anthony J.; Szabo, Csilla I.; Tamimi, Rulla M; Tan, Yen; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo Hwang; Terry, Mary Beth; Tessier, Daniel C.; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E.; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan P.; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J.; Van Den Berg, David; Van Den Ouweland, Ans M W; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N.; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S.; Wijnen, Juul T.; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H.; Xia, Lucy; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, B.; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R.; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K.; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K.; Droit, Arnaud; Bader, Gary D.; Pharoah, Paul D. P.; Couch, Fergus J.; Easton, Douglas F.; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K.; Antoniou, Antonis C.; Simard, Jacques

    2017-01-01

    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414

  18. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

    NARCIS (Netherlands)

    Milne, Roger L.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindstrom, Sara; Hui, Shirley; Lemacon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K.; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M.; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomaki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B.; Amos, Christopher I.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J.; Auber, Bernd; Auer, Paul L.; Ausems, Margreet G. E. M.; Azzollini, Jacopo; Bacot, Francois; Balmana, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B.; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W.; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R.; Blok, Marinus J.; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V.; Bojesen, Anders; Bojesen, Stig E.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R.; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Bruening, Thomas; Burwinkel, Barbara; Buys, Saundra S.; Byun, Jinyoung; Cai, Qiuyin; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D.; Esteban Castelao, J.; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B. M.; Clarke, Christine L.; Conner, Thomas; Conroy, Don M.; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G.; Cross, Simon S.; Cuk, Katarina; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F.; Domchek, Susan M.; Dorfling, Cecilia M.; Doerk, Thilo; dos-Santos-Silva, Isabel; Dubois, Stephane; Dugue, Pierre-Antoine; Dumont, Martine; Dunning, Alison M.; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A.; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D.; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D.; Ganz, Patricia A.; Gapstur, Susan M.; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Saenz, Jose A.; Gaudet, Mia M.; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; Gonzalez-Neira, Anna; Goodfellow, Paul; Greene, Mark H.; Alnaes, Grethe I. Grenaker; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guenel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Hakansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V. O.; Harrington, Patricia; Hart, Steven N.; Hartikainen, Jaana M.; Healey, Catherine S.; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Bob; Hopper, John L.; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J.; Humphreys, Keith; Hunter, David J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M.; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J.; Kets, Carolien M.; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I.; Kim, Sung-Won; Knight, Julia A.; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N.; Kruse, Torben A.; Kwong, Ava; Laenkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T.; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J.; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E.; Manoukian, Siranoush; Manson, JoAnn E.; Margolin, Sara; Martens, John W. M.; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menendez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F.; Nordestgaard, Borge G.; Norman, Aaron; Nussbaum, Robert L.; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Olswold, Curtis; Ong, Kai-ren; Oosterwijk, Jan C.; Orr, Nick; Osorio, Ana; Pankratz, V. Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Sokilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I. A.; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M.; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E.; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Angel Pujana, Miquel; Pylkas, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S.; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C.; Romero, Atocha; Romm, Jane; Rookus, Matti A.; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P.; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Daniel F.; Schoemaker, Minouk J.; Schumacher, Fredrick; Schuermann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J.; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J.; Shu, Xiao-Ou; Side, Lucy E.; Singer, Christian F.; Sohn, Christof; Southey, Melissa C.; Spinelli, John J.; Spurdle, Amanda B.; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I.; Tamimi, Rulla M.; Tan, Yen Y.; Taylor, Jack A.; Tejada, Maria-Isabel; Tengstrom, Maria; Teo, Soo H.; Terry, Mary B.; Tessier, Daniel C.; Teule, Alex; Thoene, Kathrin; Thull, Darcy L.; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E.; Tollenaar, Rob A. E. M.; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Therese; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J.; Van Den Berg, David; van den Ouweland, Ans M. W.; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R.; Weitzel, Jeffrey N.; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S.; Wijnen, Juul T.; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H.; Xia, Lucy; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K.; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Hakan; Teixeira, Manuel R.; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K.; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K.; Droit, Arnaud; Bader, Gary D.; Pharoah, Paul D. P.; Couch, Fergus J.; Easton, Douglas F.; Kraft, Peter; Chenevix-Trench, Georgia; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Antoniou, Antonis C.; Simard, Jacques

    2017-01-01

    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers

  19. Two ligands signal through the Drosophila PDGF/VEGF receptor to ensure proper salivary gland positioning.

    Science.gov (United States)

    Harris, Katherine E; Schnittke, Nikolai; Beckendorf, Steven K

    2007-07-01

    The Drosophila embryonic salivary gland is a migrating tissue that undergoes a stereotypic pattern of migration into the embryo. We demonstrate that the migratory path of the salivary gland requires the PDGF/VEGF pathway. The PDGF/VEGF receptor, Pvr, is strongly expressed in the salivary glands, and Pvr mutations cause abnormal ventral curving of the glands, suggesting that Pvr is involved in gland migration. Although the Pvr ligands, Pvf1 and Pvf2, have distinct expression patterns in the Drosophila embryo, mutations for either one of the ligands result in salivary gland migration defects similar to those seen in embryos that lack Pvr. Rescue experiments indicate that the PDGF/VEGF pathway functions autonomously in the salivary gland. The results of this study demonstrate that the Drosophila PDGF/VEGF pathway is essential for proper positioning of the salivary glands.

  20. Napsin A and Thyroid Transcription Factor-1-Positive Cerebellar Tumor with Epidermal Growth Factor Receptor Mutation

    Directory of Open Access Journals (Sweden)

    Taiji Kuwata

    2011-12-01

    Full Text Available We present a very rare case of cerebellar metastasis of unknown origin, in which a primary lung adenocarcinoma was diagnosed by pathological examination of a cerebellar metastatic tumor, using immunohistochemical markers and epidermal growth factor receptor (EGFR mutation of primary lung cancer. A 69-year-old woman was admitted to our hospital because of a hemorrhagic cerebellar tumor and multiple small brain tumors. She underwent cerebellar tumor resection. On pathological examination, the tumor was diagnosed as adenocarcinoma. However, the primary tumor site was unidentifiable even with several imaging inspections. On immunohistochemical analysis, the resected tumor was positive for napsin A and thyroid transcription factor-1. In addition, an EGFR mutation was detected in the tumor. Therefore, primary lung cancer was diagnosed and the patient was started on gefitinib (250 mg/day therapy.

  1. Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.

    Directory of Open Access Journals (Sweden)

    Gonzalo E Yévenes

    Full Text Available Glycine receptors (GlyRs are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA are positive modulators of α(1, α(2 and α(3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly potentiate α(1 GlyRs but inhibit α(2 and α(3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM region 2 and intracellular lysine 385 determine the positive modulation of α(1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1 GlyRs, without affecting inhibition of α(2 and α(3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.

  2. Estrogen receptor testing and 10-year mortality from breast cancer: A model for determining testing strategy

    Directory of Open Access Journals (Sweden)

    Christopher Naugler

    2012-01-01

    Full Text Available Background: The use of adjuvant tamoxifen therapy in the treatment of estrogen receptor (ER expressing breast carcinomas represents a major advance in personalized cancer treatment. Because there is no benefit (and indeed there is increased morbidity and mortality associated with the use of tamoxifen therapy in ER-negative breast cancer, its use is restricted to women with ER expressing cancers. However, correctly classifying cancers as ER positive or negative has been challenging given the high reported false negative test rates for ER expression in surgical specimens. In this paper I model practice recommendations using published information from clinical trials to address the question of whether there is a false negative test rate above which it is more efficacious to forgo ER testing and instead treat all patients with tamoxifen regardless of ER test results. Methods: I used data from randomized clinical trials to model two different hypothetical treatment strategies: (1 the current strategy of treating only ER positive women with tamoxifen and (2 an alternative strategy where all women are treated with tamoxifen regardless of ER test results. The variables used in the model are literature-derived survival rates of the different combinations of ER positivity and treatment with tamoxifen, varying true ER positivity rates and varying false negative ER testing rates. The outcome variable was hypothetical 10-year survival. Results: The model predicted that there will be a range of true ER rates and false negative test rates above which it would be more efficacious to treat all women with breast cancer with tamoxifen and forgo ER testing. This situation occurred with high true positive ER rates and false negative ER test rates in the range of 20-30%. Conclusions: It is hoped that this model will provide an example of the potential importance of diagnostic error on clinical outcomes and furthermore will give an example of how the effect of that

  3. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Abdel-Razeq H

    2016-10-01

    Full Text Available Hikmat Abdel-RazeqDepartment of Internal Medicine, King Hussein Cancer Center, Amman, JordanI read with great interest the review written elegantly by Gradishar addressing the challenges that community oncologists face in treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor-2 (HER2-negative advanced breast cancer in your journal.1As the author correctly stated, resistance to endocrine therapy in women with hormone receptor-positive disease is very frequent and almost inevitable.Understanding the multiple known mechanisms for endocrine resistance has helped physicians and researchers target these pathways.2 Many of the recently introduced drugs, such as the mTOR inhibitor everolimus3 and the cyclin-dependent kinase (CDK 4/6 inhibitor palbociclib,4 are in clinical practice and have been already incorporated in international guidelines.5View original paper by Gradishar.

  4. 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

  5. Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Erritzoe, David; Juul, Anders

    2010-01-01

    the effect of plasma sex hormone levels on neocortical 5-HT2A receptor binding as imaged with [18F]altanserin PET. The effect of endogenous sex-hormone levels was evaluated by multiple linear regression analysis. Results: Mean neocortical 5-HT2A receptor binding was positively correlated with estradiol (p...... = 0.0001), whereas no independent effects of testosterone could be demonstrated. Correction for other factors of importance for 5-HT2A receptor binding did not change the result. A voxel-based analysis suggested that there were no regional differences in the estradiol effect on cortical 5-HT2A...

  6. Biological response to hormonal manipulation in oestrogen receptor positive ductal carcinoma in situ of the breast

    National Research Council Canada - National Science Library

    Boland, G P; McKeown, A; Chan, K C; Prasad, R; Knox, W F; Bundred, N J

    2003-01-01

    ...) to reduce local recurrence, despite 50% of lesions being oestrogen receptor (OR) negative. We have investigated the response to hormone manipulation in DCIS by studying changes in epithelial proliferation and progesterone receptor...

  7. Arabidopsis cysteine-rich receptor-like kinase 45 positively regulates disease resistance to Pseudomonas syringae.

    Science.gov (United States)

    Zhang, Xiujuan; Han, Xiaomin; Shi, Rui; Yang, Guanyu; Qi, Liwang; Wang, Ruigang; Li, Guojing

    2013-12-01

    Arabidopsis cysteine-rich receptor-like protein kinase 45 (CRK45) was found to be involved in ABA signaling in Arabidopsis thaliana previously. Here, we reported that it also positively regulates disease resistance. The CRK45 overexpression plants increased expression of the defense genes, and enhanced resistance to Pseudomonas syringae whereas the crk45 mutant were more sensitive to P. syringae and weakened expression of the defense genes, compared to the wild type. We also found that treatment with P. syringae leads to a declined expression of CRK45 in the npr1 mutant and the NahG transgenic plants. At the same time, significantly decreased expression of CRK45 transcript in the wrky70 mutant than that in the wild type was also detected. Our results suggested that CRK45 acted as a positive regulator in Arabidopsis disease resistance, and was regulated downstream of NPR1 and WRKY70 at the transcriptional level. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  8. Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations

    Directory of Open Access Journals (Sweden)

    Lamond NW

    2014-05-01

    Full Text Available Nathan WD Lamond, Tallal YounisDepartment of Medicine, Dalhousie University at the Queen Elizabeth II Health Sciences Centre, Halifax, NS, CanadaAbstract: In the absence of specific therapy, the 15%–20% of breast cancers demonstrating human epidermal growth-factor receptor 2 (HER2 protein overexpression and/or gene amplification are characterized by a more aggressive phenotype and poorer prognosis compared to their HER2-negative counterparts. Trastuzumab (Herceptin, the first anti-HER2-targeted therapy, has been associated with improved survival outcomes in HER2-positive breast cancer. However, many patients with early stage disease continue to relapse, and metastatic disease remains incurable. In order to further improve these outcomes, several novel HER2-targeted agents have recently been developed. Pertuzumab (Perjeta, a monoclonal antibody against the HER2 dimerization domain, has also been associated with improved patient outcomes in clinical trials, and has recently been approved in combination with chemotherapy and trastuzumab for neoadjuvant therapy of early stage, HER2-positive breast cancer and first-line treatment of metastatic disease. This review briefly summarizes pertuzumab's clinical development as well as the published evidence supporting its use, and highlights some of the currently unanswered questions that will influence pertuzumab’s incorporation into clinical practice.Keywords: HER2/neu, clinical trials, drug development, novel therapies, targeted anticancer therapy

  9. Progesterone Negatively Regulates BCRP in Progesterone Receptor-Positive Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xiaojuan Wu

    2013-08-01

    Full Text Available Background/Aims: Breast cancer resistance protein (BCRP plays a crucial role in multidrug resistance (MDR. Previous studies have shown that steroid hormones, like progesterone (PROG, regulate BCRP expression. The presence of a progesterone response element (PRE in the BCRP promoter, suggests that PROG may regulate transcription of BCRP. Methods: To investigate the role of PROG in the regulation of BCRP expression, two constructs encoding full-length BCRP driven by either an endogenous PRE promoter or a constitutive CMV promoter, were transfected into T47D cells that express the progesterone receptor (PR or into PR-negative MDA-MB-231 cells. Results: After treatment with PROG, qPCR and Western blotting analyses indicated that BCRP mRNA and BCRP protein levels were significantly reduced in a dose-dependent manner in PR-positive cells, but PROG had no significant effect on BCRP levels in the PR-negative cells. The effect observed in PR-positive cells was reversed by co-treatment with RU-486, a specific PROG inhibitor. Cytometric analysis confirmed that BCRP-mediated drug efflux was inhibited and chemosensitivity to mitoxantrone was markedly increased by PROG treatment. Conclusion: These results suggest that PROG reverses BCRP-mediated MDR by down-regulating BCRP expression in breast cancer cells by affecting transcription from the PRE-containing BCRP promoter. Our studies suggest that breast cancer patients with BCRP-mediated MDR may be successfully treated with PROG.

  10. Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer.

    Science.gov (United States)

    Sotelo, Miguel J; García-Sáenz, Jose Angel; Manso, Luis; Moreno, Fernando; Ciruelos, Eva; Callata, Hector R; Mendiola, Cesar; Cabezas, Santiago; Ghanem, Ismael; Díaz-Rubio, Eduardo

    2014-01-01

    Dual human epidermal growth factor receptor 2 (HER2) blockade has been preclinically and clinically assessed in HER2-overexpressing metastatic breast cancer (mBC) with encouraging results. This is a descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing mBC from two centers. The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess progression-free survival (PFS) and overall survival. A total of 23 HER2-positive mBC patients previously treated with trastuzumab received a trastuzumab plus lapatinib based therapy. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%), whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. ORR was 22% (5/23) and 39% (9/23) of patients had stable disease. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, whereas PFS in patients with HT was 2 months. Grade≥3 adverse events were diarrhea (26%) and hand-and-foot syndrome (9%). These findings suggest that dual HER2 blockade in combination with CT is feasible in pretreated HER2-positive mBC patients.

  11. Brain metastasis in human epidermal growth factor receptor 2-positive breast cancer: from biology to treatment

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Tae Ryool [Dept. of Radiation Oncology, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon (Korea, Republic of); Kim, In Ah [Dept. of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of)

    2016-03-15

    Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents.

  12. Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

    Science.gov (United States)

    Servant, Guy; Tachdjian, Catherine; Tang, Xiao-Qing; Werner, Sara; Zhang, Feng; Li, Xiaodong; Kamdar, Poonit; Petrovic, Goran; Ditschun, Tanya; Java, Antoniette; Brust, Paul; Brune, Nicole; DuBois, Grant E.; Zoller, Mark; Karanewsky, Donald S.

    2010-01-01

    To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cell-based assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 μM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3- to 2.5-fold at 50 μM. Further assay-guided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE-2 (50 μM) and SE-3 (200 μM) increased sucralose and sucrose potencies in the assay by 24- and 4.7-fold, respectively. In human taste tests, 100 μM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 μM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste. PMID:20173092

  13. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.

    Science.gov (United States)

    Toska, Eneda; Osmanbeyoglu, Hatice U; Castel, Pau; Chan, Carmen; Hendrickson, Ronald C; Elkabets, Moshe; Dickler, Maura N; Scaltriti, Maurizio; Leslie, Christina S; Armstrong, Scott A; Baselga, José

    2017-03-24

    Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer. Copyright © 2017, American Association for the Advancement of Science.

  14. Real-World Treatment Patterns for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer in Europe and the United States.

    Science.gov (United States)

    Caldeira, Rita; Scazafave, Mark

    2016-01-01

    Clinical guidelines generally recommend endocrine therapy over chemotherapy for hormone receptor-positive advanced breast cancer (unless life-threatening metastases are present). This study aimed to assess the real-world treatment patterns of patients with hormone receptor-positive advanced breast cancer in Europe and the United States. Treatment patterns in Europe (France, Germany, Italy, Spain, and the UK) and the United States from January 2012 to December 2014 were investigated using a patient record database (Global Oncology Monitor©). Sample data were projected to the wider clinical population to provide running annual estimates every 3 months. Sample sizes ranged from 1272 to 1640 patients in Europe and from 2225 to 2760 patients in the United States. Across all lines of therapy, 37-43% (Europe) and 45-50% (United States) of patients received chemotherapy. More patients received endocrine therapy than chemotherapy as first-line treatment for advanced breast cancer (Europe: 51-54% vs. 33-35%; United States: 53-60% vs. 34-42%). In contrast, endocrine therapy-only regimens were given less commonly than chemotherapy-only regimens in the third-line setting in both Europe and the United States. Chemotherapy is used extensively in routine clinical practice for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The results also suggest that the treatment patternsin Europe and the United States are qualitatively different. Funding : Ipsos Healthcare and AstraZeneca.

  15. Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

    Science.gov (United States)

    Mangini, Neha S; Wesolowski, Robert; Ramaswamy, Bhuvaneswari; Lustberg, Maryam B; Berger, Michael J

    2015-11-01

    To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer. © The Author(s) 2015.

  16. Positive Modulation of GABAB Receptors Decreased Nicotine Self-administration and Counteracted Nicotine-induced Enhancement of Brain Reward Function in Rats

    OpenAIRE

    Paterson, Neil E.; Vlachou, Styliani; Guery, Sebastien; Kaupmann, Klemens; Froestl, Wolfgang; Markou, Athina

    2008-01-01

    Acute administration of γ-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin self-administration, and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABAB receptor positive modulators may represent potentially improved therapeutic compounds because of their fewer side-effects than receptor agonists. The present study investigated the effects of administration of the GABAB receptor positive modulators 2,6-Di...

  17. Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study.

    Science.gov (United States)

    McCullough, Ann E; Dell'orto, Patrizia; Reinholz, Monica M; Gelber, Richard D; Dueck, Amylou C; Russo, Leila; Jenkins, Robert B; Andrighetto, Stefania; Chen, Beiyun; Jackisch, Christian; Untch, Michael; Perez, Edith A; Piccart-Gebhart, Martine J; Viale, Giuseppe

    2014-02-01

    Choice of therapy for breast cancer relies on human epidermal growth factor receptor-2 (HER2) and estrogen receptor α (ER) status. Before randomization in the phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial for HER2-positive disease, HER2 and ER were centrally reviewed by Mayo Clinic (Rochester, MN, and Scottsdale, AZ) for North America and by the European Institute of Oncology (IEO; Milan, Italy) for the rest of world (except China). Discordance rates (local vs. central review) differed between Mayo and IEO. Among locally HER2-positive cases, 5.8 % (Mayo) and 14.5 % (IEO) were centrally HER2 negative. Among locally ER-positive cases, 16.2 % (Mayo) and 4.2 % (IEO) were centrally ER-negative. Among locally ER-negative cases, 3.4 % (Mayo) and 21.4 % (IEO) were centrally ER-positive. We, therefore, performed a ring study to identify features contributing to these differing discordance rates. Mayo and IEO exchanged slides for 25 HER2 and 35 ER locally/centrally discordant cases. Both laboratories performed IHC and FISH for HER2 using the HercepTest(®) and PathVysion HER2 DNA probe kit/HER2/centromere 17 probe mixture. IHC for ER was tested centrally using the monoclonal ER 1D5 antibody (Mayo) or the DAKO cocktail of ER 1D5 and 2.123 antibodies (IEO). Mayo and IEO confirmed the central HER2-negative result in 100 % of 25 cases. Mayo and IEO confirmed the central ER result in 29 (85 %) of 34 evaluable cases. The five Mayo-negative/IEO-positive cases were ER-positive when retested at Mayo using the DAKO ER cocktail. In this ring study, ALTTO ineligibility did not change when HER2 testing was performed by either IEO or Mayo central laboratories. However, a dual antibody ER assay had fewer false-negative test results than an assay with a single antibody, and there was more discordance between the two ER reagents than has been previously reported. Using even slightly different assay methods yielded different results, even between

  18. Comparison of risk classification between EndoPredict and MammaPrint in ER-positive/HER2-negative primary invasive breast cancer

    Science.gov (United States)

    Peláez-García, Alberto; Yébenes, Laura; Berjón, Alberto; Angulo, Antonia; Zamora, Pilar; Sánchez-Méndez, José Ignacio; Espinosa, Enrique; Redondo, Andrés; Heredia-Soto, Victoria; Mendiola, Marta; Feliú, Jaime

    2017-01-01

    Purpose To compare the concordance in risk classification between the EndoPredict and the MammaPrint scores obtained for the same cancer samples on 40 estrogen-receptor positive/HER2-negative breast carcinomas. Methods Formalin-fixed, paraffin-embedded invasive breast carcinoma tissues that were previously analyzed with MammaPrint as part of routine care of the patients, and were classified as high-risk (20 patients) and low-risk (20 patients), were selected to be analyzed by the EndoPredict assay, a second generation gene expression test that combines expression of 8 genes (EP score) with two clinicopathological variables (tumor size and nodal status, EPclin score). Results The EP score classified 15 patients as low-risk and 25 patients as high-risk. EPclin re-classified 5 of the 25 EP high-risk patients into low-risk, resulting in a total of 20 high-risk and 20 low-risk tumors. EP score and MammaPrint score were significantly correlated (p = 0.008). Twelve of 20 samples classified as low-risk by MammaPrint were also low-risk by EP score (60%). 17 of 20 MammaPrint high-risk tumors were also high-risk by EP score. The overall concordance between EP score and MammaPrint was 72.5% (κ = 0.45, (95% CI, 0.182 to 0.718)). EPclin score also correlated with MammaPrint results (p = 0.004). Discrepancies between both tests occurred in 10 cases: 5 MammaPrint low-risk patients were classified as EPclin high-risk and 5 high-risk MammaPrint were classified as low-risk by EPclin and overall concordance of 75% (κ = 0.5, (95% CI, 0.232 to 0.768)). Conclusions This pilot study demonstrates a limited concordance between MammaPrint and EndoPredict. Differences in results could be explained by the inclusion of different gene sets in each platform, the use of different methodology, and the inclusion of clinicopathological parameters, such as tumor size and nodal status, in the EndoPredict test. PMID:28886093

  19. 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.

  20. Toll-Like Receptor Transcriptome in the HPV-Positive Cervical Cancer Microenvironment

    Directory of Open Access Journals (Sweden)

    Correne A. DeCarlo

    2012-01-01

    Full Text Available The human papillomavirus (HPV directly infects cervical keratinocytes and interferes with TLR signalling. To shed light on the effect of HPV on upstream receptors, we evaluated TLRs 1–9 gene expression in HPV-negative normal and HPV-positive pre-malignant and malignant ex vivo cervical tissue. Quantitative real-time polymerase chain reaction was performed separately for epithelial and stromal tissue compartments. Differences in gene expression were analyzed by the Jonckheere-Terpstra trend test or the Student's t-test for pairwise comparison. Laser capture microdissection revealed an increase in TLR3 and a decrease in TLR1 mRNA levels in dysplastic and carcinoma epithelium, respectively. In the stroma, a trend of increasing TLR 1, 2, 5, 6, and 9 mRNA levels with disease severity was found. These findings implicate the involvement of TLR3 and TLR1 in early and late cervical carcinogenesis, respectively, suggesting that stromal upregulation of TLRs may play a role in cervical disease progression.

  1. Meta-analysis and gene set enrichment relative to er status reveal elevated activity of MYC and E2F in the "basal" breast cancer subgroup.

    Directory of Open Access Journals (Sweden)

    M Chehani Alles

    Full Text Available BACKGROUND: Breast cancers lacking the estrogen receptor (ER can be distinguished from other breast cancers on the basis of poor prognosis, high grade, distinctive histopathology and unique molecular signatures. These features further distinguish estrogen receptor negative (ER- tumor subtypes, but targeted therapy is currently limited to tumors over-expressing the ErbB2 receptor. METHODOLOGY/PRINCIPAL FINDINGS: To uncover the pathways against which future therapies could be developed we undertook a meta-analysis of gene expression from five large microarray datasets relative to ER status. A measure of association with ER status was calculated for every Affymetrix HG-U133A probe set and the pathways that distinguished ER- tumors were defined by testing for enrichment of biologically defined gene sets using Gene Set Enrichment Analysis (GSEA. As expected, the expression of the direct transcriptional targets of the ER was muted in ER- tumors, but the expression of genes indirectly regulated by estrogen was enhanced. We also observed enrichment of independent MYC- and E2F-driven transcriptional programs. We used a cell model of estrogen and MYC action to define the interaction between estrogen and MYC transcriptional activity in breast cancer. We found that the basal subgroup of ER- breast cancer showed a strong MYC transcriptional response that reproduced the indirect estrogen response seen in estrogen receptor positive (ER+ breast cancer cells. CONCLUSIONS/SIGNIFICANCE: Increased transcriptional activity of MYC is a characteristic of basal breast cancers where it mimics a large part of an estrogen response in the absence of the ER, suggesting a mechanism by which these cancers achieve estrogen-independence and providing a potential therapeutic target for this poor prognosis sub group of breast cancer.

  2. 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.

  3. The modified Geller-Seifter test in rats was insensitive to GABAB receptor positive modulation or blockade, or 5-HT1A receptor activation.

    Science.gov (United States)

    Paterson, Neil E; Hanania, Taleen

    2010-03-17

    Both the GABA(B) receptor positive modulator GS39783 and the GABA(B) receptor antagonist CGP46381 exhibit anxiolytic-like properties in animal models. In the present studies, the effects of GS39783 and CGP46381 in the modified Geller-Seifter task were assessed. First, the predictive validity of the task was confirmed by assessing the effects of multiple anxiolytic and non-anxiolytic compounds on punished and unpunished responding. Rats were trained in the modified Geller-Seifter task. After successful acquisition of the task, chlordiazepoxide, diazepam, MPEP, haloperidol, GS39783, 8-OH-DPAT, alprazolam and CGP46381 were tested consecutively. For each test compound, doses were administered in a randomized, counter-balanced, within-subjects design. Drug tests were performed only when rats exhibited baseline performance (the punished and time-out response rates were less than 10% of the unpunished response rate). Chlordiazepoxide, diazepam, alprazolam and MPEP released punished responding with variable effects on unpunished responding. Haloperidol had a small but significant effect on punished responding at an intermediate dose, and decreased unpunished responding at the highest dose tested. In contrast, administration of the GABA(B) receptor positive modulator GS398783 or the GABA(B) receptor antagonist CGP46381 at doses up to 30 mg/kg had no effects on either punished or unpunished responding. The 5-HT(1A) agonist 8-OH-DPAT did not release punished responding, but significantly decreased unpunished responding at the highest dose tested. The modified Geller-Seifter task generally exhibits good predictive validity for anxiolytic-like compounds. Neither GABA(B) receptor positive allosteric modulation nor blockade exhibited anxiolytic-like properties in the modified Geller-Seifter task. The 5-HT(1A) partial agonist buspirone was similarly ineffective. Copyright 2009 Elsevier B.V. All rights reserved.

  4. Changes in relative potency among positive GABA(A) receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys.

    Science.gov (United States)

    McMahon, Lance R; Javors, Martin A; France, Charles P

    2007-05-01

    Benzodiazepine treatment can result in dependence as evidenced by signs of withdrawal upon discontinuation of use. Positive GABA(A) receptor modulators were examined for their capacity to attenuate flumazenil-like discriminative stimulus effects (i.e., withdrawal) that emerge upon discontinuation of chronic benzodiazepine treatment. Rhesus monkeys receiving chronic diazepam (5.6 mg(-1) kg(-1) 24 h(-1) p.o.) discriminated flumazenil (0.1 mg/kg s.c.) from vehicle. Upon discontinuation of diazepam treatment, responding switched from the vehicle to the flumazenil lever, although at different times among monkeys. The shorter-acting benzodiazepine lorazepam (3.2 mg(-1) kg(-1) 8 h(-1)) was substituted for diazepam and, 11 h after lorazepam, monkeys consistently responded on the flumazenil lever. Flumazenil-lever responding after acute lorazepam deprivation was attenuated not only by benzodiazepines (lorazepam and midazolam) but also by positive GABA(A) receptor modulators acting at neuroactive steroid (pregnanolone and alfaxalone) and barbiturate sites (pentobarbital). Deprivation-induced responding on the flumazenil lever was not attenuated by low efficacy positive GABA(A) modulators (bretazenil and L-838,417) or non-GABA(A) receptor ligands (ketamine and cocaine). Neuroactive steroids were relatively more potent than other positive GABA(A) receptor modulators in attenuating deprivation-induced flumazenil-lever responding, as compared to their relative potency in monkeys discriminating midazolam and otherwise not receiving benzodiazepine treatment. These results suggest that positive GABA(A) receptor modulators acting at different sites attenuate withdrawal induced by discontinuation of benzodiazepine treatment, consistent with previous studies suggesting that the same compounds attenuate flumazenil-precipitated withdrawal. Differences in the relative potency of positive modulators as a function of acute versus chronic benzodiazepine treatment suggest that neuroactive

  5. Cost-Effectiveness of Lapatinib plus Letrozole in Post-Menopausal Women with Hormone Receptor-and HER2-Positive Metastatic Breast Cancer.

    Science.gov (United States)

    Delea, Thomas E; Hawkes, Carol; Amonkar, Mayur M; Lykopoulos, Konstantinos; Johnston, Stephen R D

    2013-12-01

    In the EGF30008 and TAnDEM (TrAstuzumab in Dual HER2 ER-positive Metastatic breast cancer) trials, anti-HER2 therapy plus an aromatase inhibitor (lapatinib + letrozole (LAP + LET) and trastuzumb + anastrozole (TZ + ANA), respectively) improved time to progression versus aromatase inhibitor monotherapy (LET and ANA, respectively) in post-menopausal women with previously untreated hormone receptor-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer. A partitionedsurvival analysis model using data from EGF30008 and published results of TAnDEM and other literature was used to evaluate the incremental direct medical cost per quality-adjusted life year (QALY) gained with LAP + LET versus LET, ANA, and TZ + ANA in post-menopausal women with previously untreated HR+ and HER2+ metastatic breast cancer from the UK National Health Service (NHS) perspective. Incremental costs for LAP + LET are £ 34,737 versus LET, £ 35,995 versus ANA, and £ 5,513 versus TZ + ANA. Corresponding QALYs gained are 0.467, 0.601, and 0.252 years. Cost/QALY gained with LAP + LET is £ 74,448 versus LET, £ 59,895 versus ANA, and £ 21,836 versus TZ + ANA. Given a threshold of £ 30,000/QALY, the estimated probability that LAP + LET is cost-effective is 1.4% versus LET, 9.2% versus ANA, and 51% versus TZ + ANA. Based on criteria for the evaluation of health technologies in the UK (£ 30,000/QALY), LAP + LET is not likely to be cost-effective versus aromatase inhibitor monotherapy but may be cost-effective versus TZ + ANA, although the latter comparison is associated with substantial uncertainty.

  6. ER-alpha-cDNA as part of a bicistronic transcript gives rise to high frequency, long term, receptor expressing cell clones.

    Directory of Open Access Journals (Sweden)

    Michal Shenfeld

    Full Text Available Within the large group of Estrogen Receptor alpha (ERα-negative breast cancer patients, there is a subgroup carrying the phenotype ERα(-, PR(-, and Her2(-, named accordingly "Triple-Negative" (TN. Using cell lines derived from this TN group, we wished to establish cell clones, in which ERα is ectopically expressed, forming part of a synthetic lethality screening system. Initially, we generated cell transfectants expressing a mono-cistronic ERα transcription unit, adjacent to a separate dominant selectable marker transcription unit. However, the yield of ERα expressing colonies was rather low (5-12.5%, and only about half of these displayed stable ectopic ERα expression over time. Generation and maintenance of such cell clones under minimal exposure to the ERα ligand, did not improve yield or expression stability. Indeed, other groups have also reported grave difficulties in obtaining ectopic expression of ERα in ERα-deficient breast carcinoma cells. We therefore switched to transfecting these cell lines with pERα-IRES, a plasmid vector encoding a bicistronic translation mRNA template: ERα Open Reading Frame (ORF being upstream followed by a dominant-positive selectable marker (hygro(R ORF, directed for translation from an Internal Ribosome Entry Site (IRES. Through usage of this bicistronic vector linkage system, it was possible to generate a very high yield of ERα expressing cell clones (50-100%. The stability over time of these clones was also somewhat improved, though variations between individual cell clones were evident. Our successful experience with ERα in this system may serve as a paradigm for other genes where ectopic expression meets similar hardships.

  7. Gene expression profiling analysis of bisphenol A-induced perturbation in biological processes in ER-negative HEK293 cells.

    Directory of Open Access Journals (Sweden)

    Rong Yin

    Full Text Available Bisphenol A (BPA is an environmental endocrine disruptor which has been detected in human bodies. Many studies have implied that BPA exposure is harmful to human health. Previous studies mainly focused on BPA effects on estrogen receptor (ER-positive cells. Genome-wide impacts of BPA on gene expression in ER-negative cells is unclear. In this study, we performed RNA-seq to characterize BPA-induced cellular and molecular impacts on ER-negative HEK293 cells. The microscopic observation showed that low-dose BPA exposure did not affect cell viability and morphology. Gene expression profiling analysis identified a list of differentially expressed genes in response to BPA exposure in HEK293 cells. These genes were involved in variable important biological processes including ion transport, cysteine metabolic process, apoptosis, DNA damage repair, etc. Notably, BPA up-regulated the expression of ERCC5 encoding a DNA endonuclease for nucleotide-excision repair. Further electrochemical experiment showed that BPA induced significant DNA damage in ER-positive MCF-7 cells but not in ER-negative HEK293 cells. Collectively, our study revealed that ER-negative HEK293 cells employed mechanisms in response to BPA exposure different from ER-positive cells.

  8. Functional Properties and Mechanism of Action of PPTQ, an Allosteric Agonist and Low Nanomolar Positive Allosteric Modulator at GABAA Receptors

    DEFF Research Database (Denmark)

    Madjroh, Nawid; Olander, Emma Rie; Bundgaard, Christoffer

    2017-01-01

    The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinaz...

  9. Pemetrexed improves tumor selectivity of 111In-DTPA-folate in mice with folate receptor-positive ovarian cancer

    NARCIS (Netherlands)

    C. Müller (Cristina); R. Schibli (Roger); E.P. Krenning (Eric); M. de Jong (Marion)

    2008-01-01

    textabstractFolate-based radiopharmaceuticals can be used as imaging agents and for potential radiotherapy of folate receptor (FR)-positive malignant tissue (e.g., ovarian carcinomas). However, substantial FR expression in the kidneys results in undesired renal retention of radioactivity. Recently,

  10. A fluorine-18 labeled progestin as an imaging agent for progestin receptor positive tumors with positron emission tomography

    NARCIS (Netherlands)

    Verhagen, Aalt; Elsinga, Philippus; DEGROOT, TJ; Paans, Anne; DEGOEIJ, CCJ; SLUYSER, M; Vaalburg, Willem

    The potential of the fluorine-18 labeled progestin 21-[F-18]fluoro-16-alpha-ethyl-19-norpregn-4-ene-3,20-dione ([F-18]FENP) as an imaging agent for the in vivo assessment of progestin receptor (PR) positive neoplasms with positron emission tomography has been investigated. Tissue distribution

  11. HER-2, ER, PR status concordance in primary breast cancer and corresponding metastatic lesion in lymph node in Chinese women.

    Science.gov (United States)

    Li, Min Hua; Hou, Chuan Ling; Wang, Cheng; Sun, Ai Jing

    2016-04-01

    To compare the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) in the primary site and the metastatic lesion of lymph nodes in invasive breast cancer for investigating whether the expression of these biomarkers in the primary site could act as a surrogate to the lymphatic metastatic lesion in the same patient. In lymphatic metastatic lesion and corresponding primary lesion of 107 cases of invasive breast cancer, ER and PR statuses were assessed by immunohistochemistry (IHC). HER-2 expression level was evaluated by IHC and/or fluorescence in situ hybridization (FISH). In the primary lesions, 43.9% were ER positive; 46.7% were PR positive; 34.6% were HER-2 positive. In corresponding lymphatic metastatic lesions, the HER-2 status was concordant in 90 patients; 9 patients were diagnosed positive in metastatic lesion while negative in primary lesion; 8 patients were negative in metastatic lesion while positive in primary site (agreement, 84.1%; κ=0.647). A change in ER status was observed in 24 cases: 17 cases positive in metastatic site while negative in primary site; 7 cases negative in metastatic site while positive in primary site (agreement, 77.6%; κ=0.534). PR status discordance between the primary lesion and the metastatic regional lymph nodes was reported in 19 cases (agreement, 82.2%; κ=0.640). This study revealed that there was only a moderate concordance of ER, PR and HER-2 status between primary tumors and metastatic lymph nodes. These results indicate that it was inappropriate to predict the status of ER, PR and HER-2 in metastatic lymph nodes based on the results of evaluation of that in primary lesions. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. Ovary-independent estrogen receptor expression in neonatal porcine endometrium.

    Science.gov (United States)

    Tarleton, B J; Wiley, A A; Spencer, T E; Moss, A G; Bartol, F F

    1998-04-01

    Effects of age and ovariectomy (OVX) at birth on uterine growth, endometrial development, and estrogen receptor (ER) expression were determined for intact and OVX gilts (n = 5 per day) hysterectomized on postnatal days (PND) 0, 15, 30, 60, 90, or 120. Uteri were evaluated histologically, and ER protein and mRNA expression were characterized immunohistochemically and by in situ hybridization. OVX did not affect uterine weight or endometrial thickness until after PND 60, when both increased more rapidly in intact gilts. Neither did it affect genesis of uterine glands, which were present and which proliferated after PND 0, or endometrial ER expression patterns in glandular epithelium (GE), luminal epithelium (LE), or stroma (S) between PND 0 and 120. Endometrium was ER negative at birth. On PND 15, the ER signal was strong in GE, weak in S, and effectively absent in LE. Thereafter, although the ER signal remained strong in GE and increased through PND 60 in S, it was not evident consistently until after PND 30 in LE. The data indicate that 1) porcine uterine growth and endometrial morphogenesis are ovary-independent processes before PND 60; 2) uterine gland genesis is associated temporally with development of ER-positive endometrial GE and S; and 3) regulation of endometrial ER expression is ovary independent between PND 0 and 120. The results establish the ER as a marker of GE differentiation and implicate this receptor in mechanisms regulating endometrial morphogenesis in the neonatal pig.

  13. Estrogen receptor-α36 is involved in pterostilbene-induced apoptosis and anti-proliferation in in vitro and in vivo breast cancer.

    Directory of Open Access Journals (Sweden)

    Chi Pan

    Full Text Available Pterostilbene (trans-3,5-dimethoxy-4'-hudroxystilbene is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-α66 status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-α66-negative breast cancer cells is much higher than that in ER-α66-positive breast cancer cells. ER-α36, a variant of ER-α66, is widely expressed in ER-α66-negative breast cancer, and its high expression mediates the resistance of ER-α66-positive breast cancer patients to tamoxifen therapy. The aim of the present study is to determine the relationship between the antiproliferation activity of pterostilbene and ER-α36 expression in breast cancer cells. Methyl-thiazolyl-tetrazolium (MTT assay, apoptosis analysis, and an orthotropic xenograft mouse model were used to examine the effects of pterostilbene on breast cancer cells. The expressions of ER-α36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC staining. ER-α36 knockdown was found to desensitize ER-α66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-α36 expression promotes pterostilbene-induced apoptosis in breast cancer cells. Western blot analysis data indicate that MAPK/ERK and PI3K/Akt signaling in breast cancer cells with high ER-α36 expression are mediated by ER-α36, and are inhibited by pterostilbene. These results suggest that ER-α36 is a therapeutic target in ER-α36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-α36 in the personalized therapy against ER-α36-positive breast cancer.

  14. Myoepithelial markers are expressed in at least 29% of oestrogen receptor negative invasive breast carcinoma.

    Science.gov (United States)

    Kesse-Adu, Rachel; Shousha, Sami

    2004-06-01

    Around 20% of invasive breast carcinoma are oestrogen receptor alpha (ER) negative. Theoretically, this negativity could be either due to the result of downregulation of ER expression in the tumour cells, or the result of the tumour being derived from or differentiating towards cells which normally lack that expression. Normal basal, including myoepithelial, cells of the breast are ERnegative. CD10, smooth muscle actin and S100 are markers of these basal cells that can be used for their demonstration in routinely processed sections. This study was aimed at comparing the incidence of positivity for three myoepithelial markers in ER-negative and ER-positive invasive breast carcinoma. We have examined sections of 117 cases of breast carcinoma, including 77 ER-negative and 40 ER-positive cases, for the expression of CD10, smooth muscle actin and S100, using the avidin-biotin complex immunoperoxidase technique. A tumour was considered positive if more than 10% of the tumour cells were positively stained. In all, 36 (47%) ER-negative tumours were positive for one or more of these myoepithelial markers. The percentage of positively stained tumour cells varied between 30 and 100%. Of the 40 ER-positive tumours, only three (8%) were positive; two for S100 and one for actin, with none being positive for CD10. If cases stained only with S100 are excluded, as some of these may represent luminal differentiation, definite myoepithelial differentiation seems to be present in 29% (22/77) of ER-negative tumours as compared with 2.5% (1/40) of ER-positive tumours; a difference which is highly significant (P<0.001). It is suggested that at least 29% of ER-negative invasive breast carcinomas may be derived from or differentiating along the direction of basal nonconventional luminal epithelial breast cells that normally lack the expression of ER but totally or partially express various myoepithelial markers. Such tumours might need a different therapeutic approach.

  15. Positive modulation of delta-subunit containing GABAA receptors in mouse neurons

    DEFF Research Database (Denmark)

    Vardya, Irina; Hoestgaard-Jensen, Kirsten; Nieto-Gonzalez, Jose Luis

    2012-01-01

    -free environment using Ca²⁺ imaging in cultured neurons, AA29504 showed GABA(A) receptor agonism in the absence of agonist. Finally, AA29504 exerted dose-dependent stress-reducing and anxiolytic effects in mice in vivo. We propose that AA29504 potentiates δ-containing GABA(A) receptors to enhance tonic inhibition...

  16. Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles

    NARCIS (Netherlands)

    Heukers, Raimond|info:eu-repo/dai/nl/325788103; Altintas, Isil|info:eu-repo/dai/nl/341537160; Raghoenath, Smiriti; De Zan, Erica; Pepermans, Richard; Roovers, Rob C.|info:eu-repo/dai/nl/205435599; Haselberg, Rob|info:eu-repo/dai/nl/304822647; Hennink, Wim E.|info:eu-repo/dai/nl/070880409; Schiffelers, Raymond M.|info:eu-repo/dai/nl/212909509; Kok, Robbert J.|info:eu-repo/dai/nl/170678326; Van Bergen en Henegouwen, Paul M P|info:eu-repo/dai/nl/071919481

    2014-01-01

    The hepatocyte growth factor receptor (HGFR, c-Met or Met) is a receptor tyrosine kinase that is involved in embryogenesis, tissue regeneration and wound healing. Abnormal activation of this proto-oncogene product is implicated in the development, progression and metastasis of many cancers. Current

  17. 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

  18. P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT, and MEK/ERK signaling in breast cancer

    Science.gov (United States)

    Dillon, Lloye M.; Bean, Jennifer R.; Yang, Wei; Shee, Kevin; Symonds, Lynn K.; Balko, Justin M.; McDonald, W. Hayes; Liu, Shuying; Gonzalez-Angulo, Ana M.; Mills, Gordon B.; Arteaga, Carlos L.; Miller, Todd W.

    2014-01-01

    Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth, and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology (PH) domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anti-cancer therapeutics targeting the PI3K/AKT/mTOR pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor 1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist PTEN. P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT, and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor (IGF-1R) activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in ER+ breast tumors compared to many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells. PMID:25284585

  19. Antibody Probes to Estrogen Receptor-alpha Transcript-Specific Upstream Peptides: Alternates ER-alpha Promoter Use and Breast Cancer Etiology/Outcome

    Science.gov (United States)

    2005-05-01

    cells recovered in the expressed milk of lactating healthy donors as part of a biomarkers study. Preparing for potential handling of ductal lavage...specificity for the assay (Fig. 17). It is quite feasible to isolate sufficient cells from milk samples and our potential collaorator’s lab was able...Speirs, V., 2001. Expression of alternatively spliced estrogen Uht , R.M., Webb, P., 2000. Estrogen receptor pathways to AP-I. J. receptor alpha mRNAs is

  20. 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.

  1. In vitro effects on proliferation, apoptosis and colony inhibition in ER-dependent and ER-independent human breast cancer cells by selected mushroom species.

    Science.gov (United States)

    Gu, Yu-Huan; Leonard, Jessica

    2006-02-01

    Breast cancer is the most commonly diagnosed cancer among women in Western countries. Currently, there is no effective therapy for malignant estrogen-independent breast cancer. We have screened 38 species of edible mushroom on human estrogen-receptor positive (MCF-7) and estrogen-receptor negative (MDA-MB-231, BT-20) breast cancer cells to select potential agents with broad-spectrum antitumor activity against breast cancer cells. Water-based extracts of three mushroom species, Coprinellus sp., Coprinus comatus, Flammulina velutipes (CME, CCE and FVE, respectively), were identified as novel anti-breast cancer agents. The anti-tumor activities include: 1) marked growth inhibition of both ER+ and ER- breast cancer cells; 2) induction of rapid apoptosis on both ER+ and ER- cells; 3) significant inhibition of MCF-7 tumor colony formation in vitro. The antiproliferative and cytotoxic activities of the three mushroom extracts were dose-dependent, regardless of the hormone receptor status of the cancer cells. The degree of produced cytotoxicity on ER- breast cancer cells was very high, while the IC50 of mushroom extract CME was found to be as low as 40 microg/ml on MDA-MB-231 cells and the IC50 of mushroom extract FVE was only 30 microg/ml on BT-20 cells. More interestingly, mushroom extracts CME and FVE induced an exceptionally rapid apoptosis on MCF-7 and MDA-MB-231 detected by Annexin V-FITC within 2 h of treatment and DNA fragment end-labeling assay (TUNEL) in 5 h of treatment. Anchorage-independent growth assays indicated that the MCF-7 tumor colony formation rate was reduced by 60% in CCE- and CME-treated cells and nearly completely inhibited (99%) by FVE treatment. These results suggest that mushroom species Coprinus comatus, Coprinellus sp. and Flammulina velutipes contain potent antitumor compounds for breast cancer. Our finding is important due to the lack of chemotherapeutic and chemopreventive agents for ER- human breast cancer.

  2. A Novel Melanocortin-4 Receptor Mutation MC4R-P272L Associated with Severe Obesity Has Increased Propensity To Be Ubiquitinated in the ER in the Face of Correct Folding

    Science.gov (United States)

    Granell, Susana; Serra-Juhé, Clara; Martos-Moreno, Gabriel Á.; Díaz, Francisca; Pérez-Jurado, Luis A.; Baldini, Giulia; Argente, Jesús

    2012-01-01

    Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene represent the most frequent cause of monogenic obesity in humans. MC4R mutation analysis in a cohort of 77 children with morbid obesity identified previously unreported heterozygous mutations (P272L, N74I) in two patients inherited from their obese mothers. A rare polymorphism (I251L, allelic frequency: 1/100) reported to protect against obesity was found in another obese patient. When expressed in neuronal cells, the cell surface abundance of wild-type MC4R and of the N74I and I251L variants and the cAMP generated by these receptors in response to exposure to the agonist, α-MSH, were not different. Conversely, MC4R P272L was retained in the endoplasmic reticulum and had reduced cell surface expression and signaling (by ≈3-fold). The chemical chaperone PBA, which promotes protein folding of wild-type MC4R, had minimal effects on the distribution and signaling of the P272L variant. In contrast, incubation with UBE-41, a specific inhibitor of ubiquitin activating enzyme E1, inhibited ubiquitination of MC4R P272L and increased its cell surface expression and signaling to similar levels as wild-type MC4R. UBE41 had much less profound effects on MC4R I316S, another obesity-linked MC4R variant trapped in the ER. These data suggest that P272L is retained in the ER by a propensity to be ubiquitinated in the face of correct folding, which is only minimally shared by MC4R I316S. Thus, studies that combine clinical screening of obese patients and investigation of the functional defects of the obesity-linked MC4R variants can identify specific ways to correct these defects and are the first steps towards personalized medicine. PMID:23251400

  3. A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding.

    Directory of Open Access Journals (Sweden)

    Susana Granell

    Full Text Available Heterozygous mutations in the melanocortin-4 receptor (MC4R gene represent the most frequent cause of monogenic obesity in humans. MC4R mutation analysis in a cohort of 77 children with morbid obesity identified previously unreported heterozygous mutations (P272L, N74I in two patients inherited from their obese mothers. A rare polymorphism (I251L, allelic frequency: 1/100 reported to protect against obesity was found in another obese patient. When expressed in neuronal cells, the cell surface abundance of wild-type MC4R and of the N74I and I251L variants and the cAMP generated by these receptors in response to exposure to the agonist, α-MSH, were not different. Conversely, MC4R P272L was retained in the endoplasmic reticulum and had reduced cell surface expression and signaling (by ≈ 3-fold. The chemical chaperone PBA, which promotes protein folding of wild-type MC4R, had minimal effects on the distribution and signaling of the P272L variant. In contrast, incubation with UBE-41, a specific inhibitor of ubiquitin activating enzyme E1, inhibited ubiquitination of MC4R P272L and increased its cell surface expression and signaling to similar levels as wild-type MC4R. UBE41 had much less profound effects on MC4R I316S, another obesity-linked MC4R variant trapped in the ER. These data suggest that P272L is retained in the ER by a propensity to be ubiquitinated in the face of correct folding, which is only minimally shared by MC4R I316S. Thus, studies that combine clinical screening of obese patients and investigation of the functional defects of the obesity-linked MC4R variants can identify specific ways to correct these defects and are the first steps towards personalized medicine.

  4. Accumulation of the advanced glycation end product carboxymethyl lysine in breast cancer is positively associated with estrogen receptor expression and unfavorable prognosis in estrogen receptor-negative cases.

    Science.gov (United States)

    Nass, Norbert; Ignatov, Atanas; Andreas, Ludwig; Weißenborn, Christine; Kalinski, Thomas; Sel, Saadettin

    2017-05-01

    Advanced glycation end products (AGEs) accumulate as a result of high concentrations of reactive aldehydes, oxidative stress, and insufficient degradation of glycated proteins. AGEs are therefore accepted biomarkers for aging, diabetes, and several degenerative diseases. Due to the Warburg effect and increased oxidative stress, cancer cells frequently accumulate significant amounts of AGEs. As the accumulation of AGEs may reflect the metabolic state and receptor signaling, we evaluated the potential prognostic and predictive value of this biomarker. We used immunohistochemistry to determine the AGE Nε-carboxymethyl lysine (CML) in 213 mammary carcinoma samples and Western blotting to detect AGEs in cell cultures. Whereas no significant correlation between hormone receptor status and CML was observed in cell lines, CML accumulation in tumors was positively correlated with the presence of estrogen receptor alpha, the postmenopausal state, and age. A negative correlation was found for grade III carcinomas and triple-negative cases. In a retrospective Kaplan-Meier survival analysis, there was a statistical trend that high CML accumulation correlated with a more favorable prognosis (relapse-free survival, RFS) under tamoxifen treatment (p = 0.1). In estrogen receptor-negative cases, the high CML content was significantly correlated with an unfavorable outcome (RFS) of chemotherapy (p = 0.046). CML is a therefore a potentially predictive marker for the treatment of breast cancer patients with tamoxifen or chemotherapy.

  5. POSITIVE COOPERATIVE INTERACTION OF QUATERNARY ANTICHOLINERGICS WITH FUNCTIONAL MUSCARINIC RECEPTORS IN BOVINE TRACHEAL SMOOTH-MUSCLE

    NARCIS (Netherlands)

    ROFFEL, AF; ELZINGA, CRS; BELTMAN, W; VANTINTELEN, EJJ; ZAAGSMA, J

    The interaction of quaternary anticholinergics with muscarinic receptors in bovine tracheal smooth muscle strips was investigated because some of these compounds have shown anomalous (biphasic) behaviour in radioligand displacement studies, in contrast to their tertiary analogues. It was found that

  6. 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.

  7. Hvem er vi? Hvem er de?

    DEFF Research Database (Denmark)

    Kryger, Niels

    2016-01-01

    Kommentaren tager afsæt i initiativer i de pædagogiske faglige foreninger i Europa EERA) og i Norden (NERA) og argumenterer for at det er forpligtelse for os som nordiske og europæiske pædagogiske forskere at gå op imod de stadigt mere ekskluderende vi-konstruktioner, som er blevet formuleret i for...

  8. Establishment and characterization of a new human oestradiol- and progesterone-receptor-positive mammary carcinoma serially transplantable in nude mice.

    Science.gov (United States)

    Naundorf, H; Fichtner, I; Büttner, B; Frege, J

    1992-01-01

    A human mammary carcinoma originating from a postmenopausal patient was successfully transplanted into nude mice. According to the adopted criteria the tumour proved to be oestradiol- and progesterone-receptor-positive. Histological studies of the patient tumour revealed a ductal invasive mammary carcinoma with 80% tubular growth pattern. Following transplantation the adenoid structures decreased to 30%; the mitosis rate and grade of malignancy increased. Treatment of the nude mice with 20 micrograms oestradiol benzoate/mouse caused a loss of the oestradiol receptor of the mammary carcinoma. The mammary carcinoma 3366 can be used for testing of antineoplastic substances, antihormones and for studies in regard to down-regulation or blocking of hormone receptors and possible consequences for therapies.

  9. Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER+ Breast Cancer.

    Science.gov (United States)

    Formisano, Luigi; Stauffer, Kimberly M; Young, Christian D; Bhola, Neil E; Guerrero-Zotano, Angel L; Jansen, Valerie M; Estrada, Mónica M; Hutchinson, Katherine E; Giltnane, Jennifer M; Schwarz, Luis J; Lu, Yao; Balko, Justin M; Deas, Olivier; Cairo, Stefano; Judde, Jean-Gabriel; Mayer, Ingrid A; Sanders, Melinda; Dugger, Teresa C; Bianco, Roberto; Stricker, Thomas; Arteaga, Carlos L

    2017-10-15

    Purpose:FGFR1 amplification occurs in approximately 15% of estrogen receptor-positive (ER+) human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER+/FGFR1-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR.Results: ER+/FGFR1-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER+/FGFR1-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from FGFR1-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.Conclusions: These data suggest the ERα pathway remains active in estrogen-deprived ER+/FGFR1-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists. Clin Cancer Res; 23(20); 6138-50. ©2017 AACR. ©2017 American Association for Cancer

  10. Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

    Directory of Open Access Journals (Sweden)

    Hirohiko Hikichi

    2015-03-01

    Full Text Available Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-ylphenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294, a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801 in rats. Furthermore, TASP0443294 reduced the ketamine-induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294.

  11. Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries.

    Science.gov (United States)

    Pinilla, Clemencia; Edwards, Bruce S; Appel, Jon R; Yates-Gibbins, Tina; Giulianotti, Marc A; Medina-Franco, Jose L; Young, Susan M; Santos, Radleigh G; Sklar, Larry A; Houghten, Richard A

    2013-09-01

    The formylpeptide receptor (FPR1) and formylpeptide-like 1 receptor (FPR2) are G protein-coupled receptors that are linked to acute inflammatory responses, malignant glioma stem cell metastasis, and chronic inflammation. Although several N-formyl peptides are known to bind to these receptors, more selective small-molecule, high-affinity ligands are needed for a better understanding of the physiologic roles played by these receptors. High-throughput assays using mixture-based combinatorial libraries represent a unique, highly efficient approach for rapid data acquisition and ligand identification. We report the superiority of this approach in the context of the simultaneous screening of a diverse set of mixture-based small-molecule libraries. We used a single cross-reactive peptide ligand for a duplex flow cytometric screen of FPR1 and FPR2 in color-coded cell lines. Screening 37 different mixture-based combinatorial libraries totaling more than five million small molecules (contained in 5,261 mixture samples) resulted in seven libraries that significantly inhibited activity at the receptors. Using positional scanning deconvolution, selective high-affinity (low nM K(i)) individual compounds were identified from two separate libraries, namely, pyrrolidine bis-diketopiperazine and polyphenyl urea. The most active individual compounds were characterized for their functional activities as agonists or antagonists with the most potent FPR1 agonist and FPR2 antagonist identified to date with an EC₅₀ of 131 nM (4 nM K(i)) and an IC₅₀ of 81 nM (1 nM K(i)), respectively, in intracellular Ca²⁺ response determinations. Comparative analyses of other previous screening approaches clearly illustrate the efficiency of identifying receptor selective, individual compounds from mixture-based combinatorial libraries.

  12. Effects of alpha-7 nicotinic acetylcholine receptor positive allosteric modulator on lipopolysaccharide-induced neuroinflammatory pain in mice.

    Science.gov (United States)

    Abbas, Muzaffar; Rahman, Shafiqur

    2016-07-15

    Evidence indicates that microglial activation contributes to the pathophysiology and maintenance of neuroinflammatory pain involving central nervous system alpha-7 nicotinic acetylcholine receptors. The objective of the present study was to determine the effects of 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an alpha-7 nicotinic acetylcholine receptor positive allosteric modulator (PAM), on tactile allodynia and thermal hyperalgesia following lipopolysaccharide (LPS)-induced microglial activation in hippocampus, a neuroinflammatory pain model in mice. In addition, we examined the effects of TQS on microglial activation marker, an ionized calcium-binding adapter molecule 1 (Iba-1), in the hippocampus may be associated with neuroinflammatory pain. Pretreatment of TQS (4mg/kg) significantly reduced LPS (1mg/kg)-induced tactile allodynia and thermal hyperalgesia. Moreover, pretreatment of methyllycaconitine (3mg/kg) significantly reversed TQS-induced antiallodynic and antihyperalgesic responses indicating the involvement of alpha-7 nicotinic acetylcholine receptor. Pretreatment of TQS significantly decreased LPS-induced increased in hippocampal Iba-1 expression. Overall, these results suggest that TQS reduces LPS-induced neuroinflammatory pain like symptoms via modulating microglial activation likely in the hippocampus and/or other brain region by targeting alpha-7 nicotinic acetylcholine receptor. Therefore, alpha-7 nicotinic acetylcholine receptor PAM such as TQS could be a potential drug candidate for the treatment of neuroinflammatory pain. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2008-01-01

    Background 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. Methods 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. Results 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). Conclusion The 14

  14. Expression of Vitamin D Receptor (VDR Positively Correlates with Survival of Urothelial Bladder Cancer Patients

    Directory of Open Access Journals (Sweden)

    Wojciech Jóźwicki

    2015-10-01

    Full Text Available Vitamin D3 shows tumoristatic and anticancer effects by acting through the vitamin D receptor (VDR, while hydroxylation of 25-hydroxyvitamin D3 at position 1α by CYP27B1 is an essential step in its activation. The expression of both the VDR and CYP27B1 has been found in many normal and cancer tissues, but there is a lack of information about its expression in human bladder cancers. The aim of the present research was to examine whether the expression of the VDR and CYP27B1 in bladder cancer was related to the prognostic markers and disease outcome. We analyzed VDR and CYP27B1 in samples of tumor and normal tissues obtained from 71 urinary bladder cancer patients. The highest VDR immunostaining was found in normal epithelium and was significantly lower in bladder cancer cells (p < 0.001 with Mann–Whitney U test. VDR expression was lowest in more advanced (pT2b–pT4 (p = 0.005 with Mann–Whitney U test and metastasizing cancers (p < 0.05 and p = 0.004 with Mann–Whitney U test for nuclear and cytoplasmic VDR immunostaining, respectively. The lack of cytoplasmic and nuclear VDR was also related to shorter overall survival (for cytoplasmic VDR immunolocalization 13.3 vs. 55.3 months of survival, HR = 1.92, p = 0.04 and for nuclear VDR immunostaining 13.5 vs. 55.3 months of survival, HR = 2.47, p = 0.002 with Mantel-Cox test. In cases with the lack of high cytoplasmic VDR staining the non-classic differentiations (NDs was observed in higher percentage of tumor area. CYP27B1 expression was lower in cancer cells than in normal epithelial cells (p = 0.03 with Mann–Whitney U test, but its expression did not correlate with tumor stage (pT, metastasizing, grade, mitotic activity or overall survival. In conclusion, expression of the VDR and CYP27B1 are deregulated in urothelial bladder cancers. Although our results showing a relationship between the decreased VDR expression and prognostic markers and survival time indicate potential usefulness of

  15. The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2

    NARCIS (Netherlands)

    Hong, Cynthia; Duit, Sarah; Jalonen, Pilvi; Out, Ruud; Scheer, Lilith; Sorrentino, Vincenzo; Boyadjian, Rima; Rodenburg, Kees C. W.; Foley, Edan; Korhonen, Laura; Lindholm, Dan; Nimpf, Johannes; van Berkel, Theo J. C.; Tontonoz, Peter; Zelcer, Noam

    2010-01-01

    We have previously identified the E3-ubiquitin ligase Inducible Degrader of the LDLR (Idol)1 as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by Liver X Receptors (LXRs) and its expression is responsive to cellular sterol status independent of the

  16. Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism.

    NARCIS (Netherlands)

    H. Russcher (Henk); E.F.C. van Rossum (Liesbeth); F.H. de Jong (Frank); A.O. Brinkmann (Albert); S.W.J. Lamberts (Steven); J.W. Koper (Jan)

    2005-01-01

    textabstractOne of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased

  17. Puf er plat

    DEFF Research Database (Denmark)

    Hansen, Pelle Guldborg; Zeller, Clara

    2015-01-01

    Der er stort set ingen, der har fattet, hvad nudging egentlig er. Et nudge er nemlig hverken ”et lille blidt skub”, eller ”en helt ny videnskabelig metode [der] kan ændre vores adfærd, uden vi opdager det - og uden det koster os noget”, ligesom det heller ikke er ”en måde at friste kunder til at ...

  18. Impact of size of the tumor, persistence of estrogen receptors, progesterone receptors, HER2neu receptors and Ki67 values on positivity of axillar lymph nodes at patients with early breast cancer with clinically negative axillar examination

    Directory of Open Access Journals (Sweden)

    Borislav Kondov

    2017-10-01

    Conclusion: Our study showed that the involving of the axillary lymph nodes is mainly influenced from the size of the tumor and presence of HER2neu receptors  in the univariant analysis points the important influence of positivity in the axillary lymph nodes but only size of the tumor in multivariate regressive analysis.

  19. Demokratiets krise er lovende

    DEFF Research Database (Denmark)

    Thomassen, Bjørn; Harrebye, Silas Fehmerling

    2016-01-01

    Demokratiet er i krise. Men den er langtfra bundløs. For når eksisterende partier, traditionelle virksomheder, den velkendte fagforening og de gamle medier udfordres, opstår muligheden for et sceneskift. Meget peger på, at det er på vej...

  20. Impact of palbociclib combinations on treatment of advanced estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer

    OpenAIRE

    Boér K

    2016-01-01

    Katalin Boér Department of Medical Oncology, Szent Margit Hospital, Budapest, Hungary Abstract: Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2)-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers ...

  1. Does estrogen receptor determination affect prognosis in early stage breast cancers?

    Science.gov (United States)

    Bulut, Nilufer; Altundag, Kadri

    2015-01-01

    ER+ and ER- tumors exhibit different histopathological and clinical properties. Receptor determination exists as a marker with predictive value rather than prognostic importance. Patients with invasive breast cancer (n=2849) were investigated retrospectively between 1981 and 2013. Patients were separated to four subgroups, as follows: ER+; non-luminal HER2+; ER-/PR-/HER2-; ER-PR+. We investigated the effects of ER positivity on long-term survival in breast cancers, by considering their pathological properties, surgical method applications, chemotherapy preferences, and combined hormonal treatments with regard to ER, PR and HER2 status. ER+ cases were premenopausal, and they existed with low-grade, small-sized and early stage tumors (P0.05). Furthermore, recurrence risk rose significantly when age, tumor stage and tumor grade increased (P<0.05). ER+ tumors are observed in women of advanced age, but have a good clinical response. Currently, receptor determination is still generally preferred as a practical application. ER analysis in the early stage breast cancers for women of advanced ages must be considered as an indicator of anti-estrogenic therapy administration, rather than prognostic importance. PMID:26885091

  2. Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer

    DEFF Research Database (Denmark)

    Smith, Ian; Yardley, Denise; Burris, Howard

    2017-01-01

    Purpose The Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) -positive and node-positive early breast cancer (eBC). Methods Postmenopausal women...... receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety. Results A total of 4,136 patients were randomly assigned to receive either letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709.......9% for all adverse events), hypertension (1.2% v 1.0%), hot flushes (0.8% v 0.4%), myalgia (0.8% v 0.7%), dyspnea (0.8% v 0.5%), and depression (0.8% v 0.6%). Conclusion Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in postmenopausal patients with HR...

  3. Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Schieferstein, Hanno

    2013-07-01

    Folic acid, also known as vitamin B9, is the oxidized form of 5,6,7,8-tetrahydrofolate, which serves as methyl- or methylene donor (C1-building blocks) during DNA synthesis. Under physiological conditions the required amount of 5,6,7,8-tetrahydrofolate for survival of the cell is accomplished through the reduced folate carrier (RFC). In contrast, the supply of 5,6,7,8-tetrahydrofolate is insufficient under pathophysiological conditions of tumors due to an increased proliferation rate. Consequently, many tumor cells exhibit an (over)expression of the folate receptor. This phenomenon has been applied to diagnostics (PET, SPECT, MR) to image FR-positive tumors and on the other hand to treat malignancies related to a FR (over)expression. Based on this concept, a new {sup 18}F-labeled folate for PET imaging has been developed and was evaluated in vivo using tumor-bearing mice. The incorporation of oligoethylene spacers into the molecular structure led to a significant enhancement of the pharmacokinetics in comparison to previously developed {sup 18}F-folates. The liver uptake could be reduced by one sixth by remaining a tumor uptake of 3%ID/g leading to better contrast ratios. Encouraged by these results, a clickable {sup 18}F-labeled serine-based prosthetic group has been synthesized, again with the idea to improve the metabolic and pharmacokinetic profile of hydrophilic radiotracers. Therefore, an alkyne-carrying azido-functionalized serine derivative for coupling to biomolecules was synthesized and a chlorine leaving group for {sup 18}F-labeling, which could be accomplished using a microwave-assisted synthesis, a [K is contained in 2.2.2]{sup +}/carbonate system in DMSO. Radiochemical yields of 77±6% could be achieved. The promising results obtained from the FR-targeting concept in the diagnostic field have been transferred to the boron neutron capture therapy. Therefore, a folate derivative was coupled to different boron clusters and cell uptake studies were

  4. Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice.

    Science.gov (United States)

    Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M G; Roberts, Amanda J; Markou, Athina

    2013-07-01

    γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, but this effect may be attributable to the analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Modification of cytokine-induced killer cells with chimeric antigen receptors (CARs) enhances antitumor immunity to epidermal growth factor receptor (EGFR)-positive malignancies.

    Science.gov (United States)

    Ren, Xuequn; Ma, Wanli; Lu, Hong; Yuan, Lei; An, Lei; Wang, Xicai; Cheng, Guanchang; Zuo, Shuguang

    2015-12-01

    Epidermal growth factor receptor (EGFR, ErbB1, Her-1) is a cell surface molecule overexpressing in a variety of human malignancies and, thus, is an excellent target for immunotherapy. Immunotherapy targeting EGFR-overexpressing malignancies using genetically modified immune effector cells is a novel and promising approach. In the present study, we have developed an adoptive cellular immunotherapy strategy based on the chimeric antigen receptor (CAR)-modified cytokine-induced killer (CAR-CIK) cells specific for the tumor cells expressing EGFR. To generate CAR-CIK cells, a lentiviral vector coding the EGFR-specific CAR was constructed and transduced into the CIK cells. The CAR-CIK cells showed significantly enhanced cytotoxicity and increased production of cytokines IFN-γ and IL-2 when co-cultured with EGFR-positive cancer cells. In tumor xenografts, adoptive immunotherapy of CAR-CIK cells could inhibit tumor growth and prolong the survival of EGFR-overexpressing human tumor xenografts. Moreover, tumor growth inhibition and prolonged survival in mice with EGFR(+) human cancer were associated with the increased persistence of CAR-CIK cells in vivo. Our study indicates that modification with EGFR-specific CAR strongly enhances the antitumor activity of the CIK cells against EGFR-positive malignancies.

  6. Different Use of Cell Surface Glycosaminoglycans As Adherence Receptors to Corneal Cells by Gram Positive and Gram Negative Pathogens

    Science.gov (United States)

    García, Beatriz; Merayo-Lloves, Jesús; Rodríguez, David; Alcalde, Ignacio; García-Suárez, Olivia; Alfonso, José F.; Baamonde, Begoña; Fernández-Vega, Andrés; Vazquez, Fernando; Quirós, Luis M.

    2016-01-01

    The epithelium of the cornea is continuously exposed to pathogens, and adhesion to epithelial cells is regarded as an essential first step in bacterial pathogenesis. In this article, the involvement of glycosaminoglycans in the adhesion of various pathogenic bacteria to corneal epithelial cells is analyzed. All microorganisms use glycosaminoglycans as receptors, but arranged in different patterns depending on the Gram-type of the bacterium. The heparan sulfate chains of syndecans are the main receptors, though other molecular species also seem to be involved, particularly in Gram-negative bacteria. Adherence is inhibited differentially by peptides, including heparin binding sequences, indicating the participation of various groups of Gram-positive, and -negative adhesins. The length of the saccharides produces a major effect, and low molecular weight chains inhibit the binding of Gram-negative microorganisms but increase the adherence of Gram-positives. Pathogen adhesion appears to occur preferentially through sulfated domains, and is very dependent on N- and 6-O-sulfation of the glucosamine residue and, to a lesser extent, 2-O sulfation of uronic acid. These data show the differential use of corneal receptors, which could facilitate the development of new anti-infective strategies. PMID:27965938

  7. Family environment and adult resilience: contributions of positive parenting and the oxytocin receptor gene.

    Science.gov (United States)

    Bradley, Bekh; Davis, Telsie A; Wingo, Aliza P; Mercer, Kristina B; Ressler, Kerry J

    2013-01-01

    Abundant research shows that childhood adversity increases the risk for adult psychopathology while research on influences of positive family environment on risk for psychopathology is limited. Similarly, a growing body of research examines genetic and gene by environment predictors of psychopathology, yet such research on predictors of resilience is sparse. We examined the role of positive factors in childhood family environment (CFE) and the OXTR rs53576 genotype in predicting levels of adult resilient coping and positive affect. We also examined whether the relationship between positive factors in the CFEs and adult resilient coping and positive affect varied across OXTR rs53576 genotype. We gathered self-report data on childhood environment, trauma history, and adult resilience and positive affect in a sample of 971 African American adults. We found that positive CFE was positively associated with higher levels of resilient coping and positive affect in adulthood after controlling for childhood maltreatment, other trauma, and symptoms of posttraumatic stress disorder. We did not find a direct effect of OXTR 53576 on a combined resilient coping/positive-affect-dependent variable, but we did find an interaction of OXTR rs53576 with family environment. Our data suggest that even in the face of adversity, positive aspects of the family environment may contribute to resilience. These results highlight the importance of considering protective developmental experiences and the interaction of such experiences with genetic variants in risk and resilience research.

  8. Prognostic effect of estrogen receptor status across age in primary breast cancer

    DEFF Research Database (Denmark)

    Bentzon, N.; During, M.; Rasmussen, B.B.

    2008-01-01

    Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age...... and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive...... prognostic factor over all age groups. This effect was limited to the first 5 years after diagnosis, RR: 2.08 (95% CI: 1.95-2.22, p

  9. Functional properties and mechanism of action of PPTQ, an allosteric agonist and low nanomolar positive allosteric modulator at GABAA receptors.

    Science.gov (United States)

    Madjroh, Nawid; Olander, Emma Rie; Bundgaard, Christoffer; Söderhielm, Pella Cecilia; Jensen, Anders A

    2017-11-15

    The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αβ2γ2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus laevis oocytes by two-electrode voltage clamp electrophysiology. PPTQ was found to be an allosteric agonist and a PAM (ago-PAM) at human α1β2γ2S and α4β2δ GABAARs, exhibiting intrinsic activity at micromolar concentrations and potentiating the GABA-evoked signaling through the receptors at concentrations down to the low-nanomolar range. Whereas PPTQ exclusively increased the potency of GABA at the α1β2γ2S receptor, it increased both GABA potency and efficacy at α4β2δ and displayed modest potency-based preference for α4β2δ over α1β2γ2S. In elaborate mutagenesis and competition experiments PPTQ was found to act through the same or an overlapping site as etomidate in the transmembrane β(+)/α(-) subunit interfaces, whereas it did not seem to target the other three transmembrane interfaces in the GABAAR. Finally, the PPTQ site was shown to be allosterically linked with sites targeted by neurosteroids and barbiturates but not with the high-affinity benzodiazepine site in the α1β2γ2S receptor. In conclusion, the development of a highly potent, bioavailable GABAAR ago-PAM by subtle modifications to the methaqualone scaffold demonstrates that derivatization of this infamous drug from the past can lead to modulators with distinct functional characteristics at the receptors. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects.

    Science.gov (United States)

    Ignatowska-Jankowska, Bogna M; Baillie, Gemma L; Kinsey, Steven; Crowe, Molly; Ghosh, Sudeshna; Owens, Robert A; Damaj, Imad M; Poklis, Justin; Wiley, Jenny L; Zanda, Matteo; Zanato, Chiara; Greig, Iain R; Lichtman, Aron H; Ross, Ruth A

    2015-12-01

    The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [(3)H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(35)S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.

  11. Prediction of Low versus High Recurrence Scores in Estrogen Receptor-Positive, Lymph Node-Negative Invasive Breast Cancer on the Basis of Radiologic-Pathologic Features: Comparison with Oncotype DX Test Recurrence Scores.

    Science.gov (United States)

    Dialani, Vandana; Gaur, Shantanu; Mehta, Tejas S; Venkataraman, Shambhavi; Fein-Zachary, Valerie; Phillips, Jordana; Brook, Alexander; Slanetz, Priscilla J

    2016-08-01

    Purpose To review mammographic, ultrasonographic (US), and magnetic resonance (MR) imaging features and pathologic characteristics of estrogen receptor (ER)-positive, lymph node-negative invasive breast cancer and to determine the relationship of these characteristics to Oncotype DX (Genomic Health, Redwood City, Calif) test recurrence scores (ODRS) for breast cancer recurrence. Materials and Methods This institutional review board-approved retrospective study was performed in a single large academic medical center. The study population included patients with ER-positive, lymph node-negative invasive breast cancer who underwent genomic testing from January 1, 2009, to December 31, 2013. Imaging features of the tumor were classified according to the Breast Imaging Reporting and Data System lexicon by breast imagers who were blinded to the ODRS. Mammography was performed in 86% of patients, US was performed in 84%, and MR imaging was performed in 33%, including morphologic and kinetic evaluation. Images from each imaging modality were evaluated. Each imaging finding, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, and tumor grade were then individually correlated with ODRS. Analysis of variance was used to determine differences for each imaging feature. Regression analysis was used to calculate prediction of recurrence on the basis of imaging features combined with histopathologic features. Results The 319 patients had a mean age ± standard deviation of 55 years ± 8.7 (range, 31-82 years). Imaging features with a positive correlation with ODRS included a well-circumscribed oval mass (P = .024) at mammography, vascularity (P = .047) and posterior enhancement (P = .004) at US, and lobulated mass (P = .002) at MR imaging. Recurrence scores were predicted by using these features in combination with PR and HER2 status and tumor grade by using the threshold of more than 30 as a high recurrence score. With a regression tree, there

  12. Hormone receptor status of contralateral breast cancers: analysis of data from the US SEER population-based registries.

    Science.gov (United States)

    Mezencev, Roman; Švajdler, Marián

    2017-05-01

    Women diagnosed with breast cancer display higher propensity to develop second primary cancer in the contralateral breast (CBC). Identification of patients with increased risk of CBC and understanding relationships between hormone receptor (HR) statuses of the first and second breast cancers is desirable for endocrine-based prevention strategies. Using 1992-2012 data from 13 SEER registries, the risk of developing CBC was determined as ratio of observed and expected second breast cancers (SIR). Association between HR statuses was examined by exploratory data analysis and multivariable logistic regression. Women with ER-positive and ER-negative breast cancers have increased risk of developing CBC with SIR values 2.09 (CI 95 = 1.97-2.21) and 2.40 (CI 95 = 2.18-2.63), respectively. ER statuses of the CBC are moderately positively associated. In metachronous CBC, most cases with ER-positive first cancers had ER-positive second breast cancers (81.6 %; CI 95 = 80.2-82.9 %); however, considerable proportion of cases with ER-negative first cancers had ER-positive second cancers (48.8 %; CI 95 = 46.2-51.4 %). Some women with ER-negative breast cancers may benefit from endocrine-based prevention of ER-positive CBC.

  13. Lipid-rich carcinoma of the breast that is strongly positive for estrogen receptor: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Oba T

    2016-03-01

    Full Text Available Takaaki Oba,1 Mayu Ono,1 Asumi Iesato,1 Toru Hanamura,1 Takayuki Watanabe,1 Tokiko Ito,1 Toshiharu Kanai,1 Kazuma Maeno,1 Ken-ichi Ito,1 Ayako Tateishi,2 Akihiko Yoshizawa,2 Fumiyoshi Takayama31Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, 2Department of Laboratory Medicine, Shinshu University Hospital, 3Imaging Center, Ichinose Neurosurgical Hospital, Matsumoto, JapanAbstract: Lipid-rich carcinoma (LRC of the breast is a rare breast cancer variant that accounts for <1% of all breast malignancies. It has been reported that LRCs are negative for estrogen receptor. Here, we report a case of LRC of the breast that was strongly positive for estrogen receptor and treated with endocrine adjuvant therapy. A 52-year-old postmenopausal female noticed a lump in her right breast by self-examination and presented to our hospital. Physical examination revealed an elastic 30 mm ×20 mm hard mass in the upper medial part of her right breast. The findings obtained using ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging suggested breast cancer. Core needle biopsy resulted in the diagnosis of invasive carcinoma. The patient underwent mastectomy and sentinel lymph node biopsy. Histopathologically, the tumor cells were abundant in foamy cytoplasm. Because the presence of marked cytoplasmic lipid droplets was confirmed by Sudan IV staining and electron microscopic examination of the tumor and the lipid droplets were negative for periodic acid–Schiff staining, the tumor was diagnosed as an LRC. Immunohistochemically, estrogen and progesterone receptors of the tumor were strongly positive, human epidermal growth factor receptor type 2 was negative, and the ratio of Ki-67-positive cells was ~30%. After surgery, the patient underwent combination chemotherapy with anthracycline, cyclophosphamide, and 5-fluorouracil, followed by docetaxel. Thereafter

  14. Family environment and adult resilience: contributions of positive parenting and the oxytocin receptor gene

    Directory of Open Access Journals (Sweden)

    Bekh Bradley

    2013-09-01

    Full Text Available Background: Abundant research shows that childhood adversity increases the risk for adult psychopathology while research on influences of positive family environment on risk for psychopathology is limited. Similarly, a growing body of research examines genetic and gene by environment predictors of psychopathology, yet such research on predictors of resilience is sparse. Objectives: We examined the role of positive factors in childhood family environment (CFE and the OXTR rs53576 genotype in predicting levels of adult resilient coping and positive affect. We also examined whether the relationship between positive factors in the CFEs and adult resilient coping and positive affect varied across OXTR rs53576 genotype. Methods: We gathered self-report data on childhood environment, trauma history, and adult resilience and positive affect in a sample of 971 African American adults. Results: We found that positive CFE was positively associated with higher levels of resilient coping and positive affect in adulthood after controlling for childhood maltreatment, other trauma, and symptoms of posttraumatic stress disorder. We did not find a direct effect of OXTR 53576 on a combined resilient coping/positive-affect-dependent variable, but we did find an interaction of OXTR rs53576 with family environment. Conclusions: Our data suggest that even in the face of adversity, positive aspects of the family environment may contribute to resilience. These results highlight the importance of considering protective developmental experiences and the interaction of such experiences with genetic variants in risk and resilience research.For the abstract or full text in other languages, please see Supplementary files under Article Tools online

  15. Prognostic Value of Estrogen Receptor alpha and Progesterone Receptor Conversion in Distant Breast Cancer Metastases

    NARCIS (Netherlands)

    Hoefnagel, Laurien D. C.; Moelans, Cathy B.; Meijer, S. L.; van Slooten, Henk-Jan; Wesseling, Pieter; Wesseling, Jelle; Westenend, Pieter J.; Bart, Joost; Seldenrijk, Cornelis A.; Nagtegaal, Iris D.; Oudejans, Joost; van der Valk, Paul; van Gils, Carla H.; van der Wall, Elsken; van Diest, Paul J.

    2012-01-01

    BACKGROUND: Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor alpha (ER alpha) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ER alpha and

  16. 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.

  17. Expression and prognostic value of estrogen receptor β in patients with triple-negative and triple-positive breast cancer.

    Science.gov (United States)

    Guo, Liying; Zhu, Qianwen; Aisimutuola, Mulati; Yilamu, Dilimina; Liu, Sha; Jakulin, Adina

    2015-06-01

    The aim of the present study was to investigate the expression of estrogen receptor β (ERβ) in triple-negative and triple-positive breast cancer patients, and evaluate its utility as a prognostic factor. Between January 2000 and December 2010, primary tumor tissue samples were collected from 234 subjects, including 107 triple-negative and 127 triple-positive breast cancer patients. The samples were embedded in paraffin and immunohistochemical staining was conducted to determine the expression levels of ERβ. The Kaplan-Meier method was used to analyze patient survival rates. ERβ expression was observed in 38/107 patients (35.5%) with triple-negative breast cancer and 63/127 patients (49.6%) with triple-positive breast cancer. The ERβ expression rate was significantly decreased in the patients with triple-negative breast cancer, as compared with those with triple-positive breast cancer (P=0.03). Analysis of the survival rates indicated that patients with triple-negative breast cancer and positive ERβ expression exhibited poor disease progression-free survival (DFS) compared with those with negative ERβ expression (P=0.021). However, no statistically significant difference was observed in the DFS between the triple-positive breast cancer patients with positive and negative ERβ expression. Therefore, the expression of ERβ varies between triple-negative and triple-positive breast cancer patients. In addition, positive expression of ERβ indicates a poor prognosis in triple-negative breast cancer patients; however, this is not the case for triple-positive breast cancer patients.

  18. 99mTc-EDDA/HYNIC-TOC in management of patients with head and neck somatostatin receptor positive tumors.

    Science.gov (United States)

    Trogrlic, Mate; Tezak, Stanko

    2016-01-01

    Aim of this study was to determine the value of technetium-99m-hydrazinonicotinyl-Tyr3-octreotide (99mTc-ED-DA/HYNIC-TOC) in patients with somatostatin receptor (SSR) positive tumors of head and neck region. A total number of 16 patients were enrolled in this study. Planar whole body (WB) and single photon emission computed tomography (SPECT) images were acquired at 2 and 4 hours after the injection of approximately 670 MBq of 99mTc-EDDA/HYNIC-TOC. Additional single photon emission computed tomography/computed tomography (SPECT/CT) images of the head and neck region were acquired at 4h post tracer injection. Clinical and imaging follow up were taken as the reference standard. There were 10 female and 6 male patients of age 57.7 ± 12.9 years (58.5; 32-78) years. 99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy (SRS) was TP in 13 patients, TN in two and FP in one. Follow up period for SRS was 31.1 ± 19.4 (29; 2-63) months. 99mTc-EDDA/HYNIC-TOC scintigraphy provided additional information in 50% of patients, with impact on patient management in the same percentage of patients. Distant metastases were found in nine out of 16 patients (56%). 99mTc-EDDA/HYNIC-TOC SRS had sensitivity of 100% (75.3-100%), specificity of 66.7% (9.4-99.2%), accuracy of 93.7%, positive predictive value of 92.9% (66.1-99.8%), and negative predictive value of 100% (15.8-100%). Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC is very useful imaging method in the evalu-ation of patients with SSR positive tumors of head and neck region.

  19. Apparent diffusion coefficient in estrogen receptor-positive invasive ductal breast carcinoma: correlations with tumor-stroma ratio.

    Science.gov (United States)

    Ko, Eun Sook; Han, Boo-Kyung; Kim, Rock Bum; Cho, Eun Yoon; Ahn, Soomin; Nam, Seok Jin; Ko, Eun Young; Shin, Jung Hee; Hahn, Soo Yeon

    2014-04-01

    To determine whether apparent diffusion coefficient (ADC) values vary according to tumor-stroma ratio, dominant stroma type, or presence of central fibrosis in estrogen receptor-positive breast cancer. Institutional review board approval was obtained, and patient consent was waived. Sixty-one patients with estrogen receptor-positive invasive ductal carcinoma-not otherwise specified who underwent breast magnetic resonance (MR) imaging with diffusion-weighted (DW) imaging were included in this study. The ADC values of the lesions were measured. Two pathologists evaluated the tumor-stroma ratio, dominant stroma type (collagen, fibroblast, lymphocyte), and central fibrosis. Detectability on DW images was compared between the two groups according to the tumor-stroma ratio (stroma rich or stroma poor). Mean ADC values were retrospectively compared with the tumor-stroma ratio, dominant stroma type, and presence of a central fibrosis. Multiple linear regression analysis was performed to determine variables independently associated with ADC. On DW images, detectability was not significantly different between stroma-rich and stroma-poor groups (P = .244). ADC values were significantly lower in the stroma-poor group (P collagen-dominant type were lower than in fibroblast-dominant or lymphocyte-dominant types (P = .021). In multiple linear regression analysis, tumor-stroma ratio (P = .007), tumor size (P = .007), and dominant stroma type (collagen dominant, P = .029) were independently correlated with ADC. In estrogen receptor-positive breast cancers, ADC values showed significant differences according to the tumor-stroma ratio and dominant stroma type. RSNA, 2013

  20. The role of histological subtype in hormone receptor positive metastatic breast cancer: similar survival but different therapeutic approaches.

    Science.gov (United States)

    Lobbezoo, Dorien; Truin, Wilfred; Voogd, Adri; Roumen, Rudi; Vreugdenhil, Gerard; Dercksen, Marcus Wouter; van den Berkmortel, Franchette; Smilde, Tineke; van de Wouw, Agnes; van Kampen, Roel; van Riel, Johanna; Peters, Natascha; Peer, Petronella; Tjan-Heijnen, Vivianne C G

    2016-05-17

    This study describes the differences between the two largest histological breast cancer subtypes (invasive ductal carcinoma (IDC) and invasive (mixed) lobular carcinoma (ILC) with respect to patient and tumor characteristics, treatment-choices and outcome in metastatic breast cancer. Patients with ILC were older at diagnosis of primary breast cancer and had more often initial bone metastasis (46.5% versus 34.8%, P = 0.01) and less often multiple metastatic sites compared to IDC (23.7% versus 30.9%, P = 0.11). Six months after diagnosis of metastatic breast cancer, 28.1% of patients with ILC and 39.8% of patients with IDC had received chemotherapy with a longer median time to first chemotherapy for those with ILC (P = 0.001). After six months 84.8% of patients with ILC had received endocrine therapy versus 72.5% of patients with IDC (P = 0.0001). Median overall survival was 29 months for ILC and 25 months for IDC (P = 0.53). We included 437 patients with hormone receptor-positive IDC and 131 patients with hormone receptor-positive ILC, all diagnosed with metastatic breast cancer between 2007-2009, irrespective of date of the primary diagnosis. Patient and tumor characteristics and data on treatment and outcome were collected. Survival curves were obtained using the Kaplan-Meier method. Treatment strategies of hormone receptor-positive metastatic breast cancer were remarkably different for patients with ILC and IDC. Further research is required to understand tumor behavior and treatment-choices in real-life.

  1. UTX promotes hormonally responsive breast carcinogenesis through feed-forward transcription regulation with estrogen receptor.

    Science.gov (United States)

    Xie, G; Liu, X; Zhang, Y; Li, W; Liu, S; Chen, Z; Xu, B; Yang, J; He, L; Zhang, Z; Jin, T; Yi, X; Sun, L; Shang, Y; Liang, J

    2017-09-28

    UTX is implicated in embryonic development and lineage specification. However, how this X-linked histone demethylase contributes to the occurrence and progression of breast cancer remains to be clarified. Here we report that UTX is physically associated with estrogen receptor (ER) and functions in ER-regulated transcription. We showed that UTX coordinates with JHDM1D and CBP to direct H3K27 methylation-acetylation transition and to create a permissive chromatin state on ER targets. Genome-wide analysis of the transcriptional targets of UTX by ChIP-seq identified a set of genes such as chemokine receptor CXCR4 that are intimately involved in breast cancer tumorigenesis and metastasis. We demonstrated that UTX promotes the proliferation and migration of ER(+) breast cancer cells. Interestingly, UTX itself is transactivated by ER, forming a feed-forward loop in the regulation of hormone response. Indeed, UTX is upregulated during ER(+) breast cancer progression, and the expression level of UTX is positively correlated with that of CXCR4 and negatively correlated with the overall survival of ER(+) breast cancer patients. Our study identified a feed-forward loop between UTX and ER in the regulation of hormonally responsive breast carcinogenesis, supporting the pursuit of UTX as an emerging therapeutic target for the intervention of certain ER(+) breast cancer with specific epigenetic vulnerability.

  2. 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.

  3. Computing highly correlated positions using mutual information and graph theory for G protein-coupled receptors

    National Research Council Canada - National Science Library

    Fatakia, Sarosh N; Costanzi, Stefano; Chow, Carson C

    2009-01-01

    .... A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance...

  4. Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer: a case control study.

    Science.gov (United States)

    Kodahl, Annette R; Lyng, Maria B; Binder, Harald; Cold, Søren; Gravgaard, Karina; Knoop, Ann S; Ditzel, Henrik J

    2014-07-01

    There are currently no highly sensitive and specific minimally invasive biomarkers for detection of early-stage breast cancer. MicroRNAs (miRNAs) are present in the circulation and may be unique biomarkers for early diagnosis of human cancers. The aim of this study was to investigate the differential expression of miRNAs in the serum of breast cancer patients and healthy controls. Global miRNA analysis was performed on serum from 48 patients with ER-positive early-stage breast cancer obtained at diagnosis (24 lymph node-positive and 24 lymph node-negative) and 24 age-matched healthy controls using LNA-based quantitative real-time PCR (qRT-PCR). A signature of miRNAs was subsequently validated in an independent set of 111 serum samples from 60 patients with early-stage breast cancer and 51 healthy controls and further tested for reproducibility in 3 independent data sets from the GEO Database. A multivariable signature consisting of 9 miRNAs (miR-15a, miR-18a, miR-107, miR-133a, miR-139-5p, miR-143, miR-145, miR-365, miR-425) was identified that provided considerable discrimination between breast cancer patients and healthy controls. Further, the ability of the 9 miRNA signature to stratify samples from breast cancer patients and healthy controls was confirmed in the validation set (p = 0.012) with a corresponding AUC = 0.665 in the ROC-curve analysis. No association between miRNA expression and tumor grade, tumor size, menopausal- or lymph node status was observed. The signature was also successfully validated in a previously published independent data set of circulating miRNAs in early-stage breast cancer (p = 0.024). We present herein a 9 miRNA signature capable of discriminating between ER-positive breast cancer and healthy controls. Using a specific algorithm based on the 9 miRNA signature, the risk for future individuals can be predicted. Since microRNAs are highly stable in blood components, this signature might be useful in the development of a blood

  5. Imatinib mesylate treatment for platelet-derived growth factor receptor alfa-positive choroid plexus carcinoma

    Directory of Open Access Journals (Sweden)

    Chihiro Kawakami

    2012-05-01

    Full Text Available We herein report a female child with choroid plexus carcinoma treated with standard dose of imatinib at disease recurrence. This patient failed initial twice-surgical resections, central nervous system (CNS irradiation, and adjuvant chemotherapies and high-dose thiotepa and melphalan with auto peripheral blood stem cell rescue. Finally, imatinib treatment was undergone as a palliative setting, however the tumor did not reduce and the patient died of tumor bleedings. We consider that the reasons for the failure are as follows: i adequate CNS level of imatinib were not obtained because of the blood brain barrier, ii the lack of plateletderived growth factor receptor beta expression in our case may have a crucial role.

  6. Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy

    Science.gov (United States)

    2017-11-16

    Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  7. Arabidopsis thaliana RECEPTOR DEAD KINASE1 Functions as a Positive Regulator in Plant Responses to ABA.

    Science.gov (United States)

    Kumar, Dhinesh; Kumar, Ritesh; Baek, Dongwon; Hyun, Tae-Kyung; Chung, Woo Sik; Yun, Dae-Jin; Kim, Jae-Yean

    2017-02-13

    Abscisic acid (ABA) is a major phytohormone involved in important stress-related and developmental plant processes. Membrane-delimited ABA signal transduction plays an important role in early ABA signaling, but the molecular mechanisms connecting core signaling components to the plasma membrane remain unclear. Plants have evolved a large number of receptor-like kinases (RLKs) to modulate diverse biological processes by perceiving extracellular stimuli and activating downstream signaling responses. In this study, a putative leucine-rich repeat-RLK gene named RECEPTOR DEAD KINASE1 (AtRDK1) was identified and characterized in Arabidopsis thaliana. RDK1 promoter-GUS analysis revealed that RDK1 is expressed ubiquitously in the various tissues in Arabidopsis, and its expression is mainly induced by ABA. In the presence of ABA, RDK1-deficient rdk1-1 and rdk1-2 lines showed significant resistance in cotyledon greening and root growth, whereas RDK1-overexpressing lines showed enhanced sensitivity. Consistently, the expression of ABA-responsive genes was significantly downregulated in rdk1 mutant seedlings, which were also hypersensitive to drought stress with increased water loss. Interestingly, RDK1 was found to be an atypical kinase localized to the plasma membrane and did not require its kinase activity during ABA-mediated inhibition of seedling development. Accordingly, RDK1 interacted in the plasma membrane with type 2C protein phosphatase ABSCISIC ACID INSENSITIVE1 (ABI1); this interaction was further enhanced by exogenous application of ABA, suggesting that RDK1-mediated recruitment of ABI1 onto the plasma membrane is important for ABA signaling. Taken together, these results reveal an important role for RDK1 in plant responses to abiotic stress conditions in an ABA-dependent manner. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

  8. 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

    Expression of HOX transcript antisense intergenic RNA (HOTAIR)-a long non-coding RNA-has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR...... serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients....

  9. Hvornår er agil projektledelse rigtig?

    DEFF Research Database (Denmark)

    Pries-Heje, Jan

    2011-01-01

    Styrken ved agil projektledelse er hurtigheden og muligheden for at absorbere ændringer hurtigt gennem hele projektets løbetid, men der er naturligvis også nogle svagheder. Nogle af dem nævner jeg i artiklen, men derudover egner agil-formen sig ikke specielt godt til komplicerede projekter, hvor...... liv eller mange penge er på spil. Agil-formen er heller ikke velegnet til umotiverede medarbejdere, fordi de ikke har noget at bidrage med. For en projektleder synes jeg, at det er væsentligt at have et dybdegående kendskab til positive og negative sider ved både agil og plandreven projektledelse....... Verden er kompleks, og vores projekter derfor er tilsvarende komplekse. Som projektleder bør man således kunne analysere sig frem til den rigtige form for projektledelse, uanset om det er agil projektledelse eller ej....

  10. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies.

    Science.gov (United States)

    Jung, Seungyoun; Wang, Molin; Anderson, Kristin; Baglietto, Laura; Bergkvist, Leif; Bernstein, Leslie; van den Brandt, Piet A; Brinton, Louise; Buring, Julie E; Eliassen, A Heather; Falk, Roni; Gapstur, Susan M; Giles, Graham G; Goodman, Gary; Hoffman-Bolton, Judith; Horn-Ross, Pamela L; Inoue, Manami; Kolonel, Laurence N; Krogh, Vittorio; Lof, Marie; Maas, Paige; Miller, Anthony B; Neuhouser, Marian L; Park, Yikyung; Robien, Kim; Rohan, Thomas E; Scarmo, Stephanie; Schouten, Leo J; Sieri, Sabina; Stevens, Victoria L; Tsugane, Schoichiro; Visvanathan, Kala; Wilkens, Lynne R; Wolk, Alicja; Weiderpass, Elisabete; Willett, Walter C; Zeleniuch-Jacquotte, Anne; Zhang, Shumin M; Zhang, Xuehong; Ziegler, Regina G; Smith-Warner, Stephanie A

    2016-06-01

    Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts. During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model. Alcohol consumption was positively associated with risk of ER+ and ER- breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing ≥ 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER- breast cancer (Ptrend ≤ 0.001; Pcommon-effects by ER status: 0.57). Associations were similar for alcohol intake from beer, wine and liquor. The associations with alcohol intake did not vary significantly by total (from foods and supplements) folate intake (Pinteraction ≥ 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER- breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status. Alcohol consumption was positively associated with risk of both ER+ and ER- breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

  11. Beyond risk: Prospective effects of GABA Receptor Subunit Alpha-2 (GABRA2) × Positive Peer Involvement on adolescent behavior.

    Science.gov (United States)

    Trucco, Elisa M; Villafuerte, Sandra; Burmeister, Margit; Zucker, Robert A

    2017-08-01

    Research on Gene × Environment interactions typically focuses on maladaptive contexts and outcomes. However, the same genetic factors may also impact susceptibility to positive social contexts, leading to adaptive behavior. This paper examines whether the GABA receptor subunit alpha-2 (GABRA2) single nucleotide polymorphism rs279858 moderates the influence of positive peer affiliation on externalizing behavior and various forms of competence. Regions of significance were calculated to determine whether the form of the interaction supported differential susceptibility (increased sensitivity to both low and high positive peer affiliation) or vantage sensitivity (increased sensitivity to high positive peer affiliation). It was hypothesized that those carrying the homozygous minor allele (GG) would be more susceptible to peer effects. A sample (n = 300) of primarily male (69.7%) and White (93.0%) adolescents from the Michigan Longitudinal Study was assessed from ages 12 to 17. There was evidence for prospective Gene × Environment interactions in three of the four models. At low levels of positive peer involvement, those with the GG genotype were rated as having fewer adaptive outcomes, while at high levels they were rated as having greater adaptive outcomes. This supports differential susceptibility. Conceptualizing GABRA2 variants as purely risk factors may be inaccurate. Genetic differences in susceptibility to adaptive environmental exposures warrants further investigation.

  12. The androgen receptor and estrogen receptor

    NARCIS (Netherlands)

    Oosterkamp, H.M.; Bernards, R.A.

    2002-01-01

    The androgen receptor (AR) and the estrogen receptors (ER) are members of the nuclear receptor (NR) family. These NRs are distinguished from the other transcription factors by their ability to control gene expression upon ligand binding (steroids, retinoids, thyroid hormone, vitamin D, fatty

  13. Estrogen receptor, progesterone receptor, and human epidermal ...

    African Journals Online (AJOL)

    Current clinical practice employs the use of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as biomarkers to appropriately select patients that would benefit from targeted therapy against these major molecular pathways of the disease. This study aims at ...

  14. Functional repression of estrogen receptor a by arsenic trioxide in human breast cancer cells.

    Science.gov (United States)

    Chen, Gui-Cai; Guan, Li-Shuang; Hu, Wei-Lian; Wang, Zhao-Yi

    2002-01-01

    When estrogen binds its receptor (ER), it becomes a potent mitogen in a number of target tissues including the mammary gland where it plays an important role in the pathogenesis of mammary carcinoma. Arsenic trioxide (AS2O3), a clinically effective agent against acute promyelocytic leukemia, has been shown to induce apoptosis in a variety of cancer cells in vitro. Here, we investigated the effects of AS2O3 on the growth of two ER-positive breast cancer cell lines, MCF7 and T47D in vitro. We found that higher doses of AS2O3 dramatically reduced the survival of these two breast cancer cell lines while lower doses of AS2O3 significantly inhibited the expression of estrogen receptor alpha (ER-alpha), but did not effect ER-beta expression. The ER-alpha expression is totally restored when AS2O3 is absent for 24 hours. Using a reporter gene controlled by ER, we further demonstrated that AS2O3 strongly-repressed 17beta-estradiol (E2) stimulated-transcriptional activation. Moreover, AS2O3 abolished transcriptional induction of the estrogen responsive gene pS2 mediated by E2. These results indicated that AS2O3 specifically inhibits expression and signaling pathway of the ER-alpha. We suggest that AS2O3 in combination with other methods might provide a novel therapeutic approach for ER-alpha-positive breast cancer.

  15. Vreden er over os

    DEFF Research Database (Denmark)

    Mehlsen, Camilla

    2006-01-01

    Urolige elever, cyklister - der giver fuck-finger, aggressive demonstranter. Samtiden er på vej ind i en æra domineret af vrede, siger rektor Lars-Henrik Schmidt, der er aktuel med bogen 'Om vreden'. Udgivelsesdato: Juni...

  16. Chemotherapy-induced amenorrhea and the resumption of menstruation in premenopausal women with hormone receptor-positive early breast cancer.

    Science.gov (United States)

    Koga, Chinami; Akiyoshi, Sayuri; Ishida, Mayumi; Nakamura, Yoshiaki; Ohno, Shinji; Tokunaga, Eriko

    2017-09-01

    For premenopausal women with breast cancer, information on the effects of chemotherapy and the risk of infertility is important. In this study, the effect of chemotherapy on the ovarian function in premenopausal women with hormone receptor-positive breast cancer was investigated, with an age-stratified analysis of the appearance of amenorrhea and the resumption of menstruation after the use of chemotherapy with anthracyclines or taxanes. Premenopausal women diagnosed with operable Stage I-III hormone receptor-positive breast cancer and underwent neoadjuvant or adjuvant chemotherapy with the standard regimen of anthracyclines and/or taxanes were included. The patients were classified into age groups in 5-year increments, and the rates of chemotherapy-induced amenorrhea (CIA), resumption of menstruation, and duration of CIA after chemotherapy were analyzed. The subjects consisted of 101 patients (median age 45 years). CIA occurred in 97 (96%) patients and 40 patients resumed menstruation. In all patients aged ≤39 years menstruation restarted, whereas in all patients aged ≥50 years, menstruation did not restart. For the patients who resumed menstruation, the younger the patients, the sooner menstruation tended to restart. The resumption of menstruation occurred within 1 year for younger patients aged around 30 years, but for those aged ≥35 years, 60% of cases took around 2-3 years for resumption. The incidence of CIA, the resumption of menstruation and duration of CIA after chemotherapy depend greatly on the patient's age.

  17. Bradykinin B2-receptor-mediated positive chronotropic effect of bradykinin in isolated rat atria

    NARCIS (Netherlands)

    Li, Q.; Zhang, J.; Loro, J. F.; Pfaffendorf, M.; van Zwieten, P. A.

    1998-01-01

    The positive chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35+/-4 beats/min, approximately 25% of the 1

  18. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

    Science.gov (United States)

    Jiang, Xi; Deng, Ke-Qiong; Luo, Yuxuan; Jiang, Ding-Sheng; Gao, Lu; Zhang, Xiao-Fei; Zhang, Peng; Zhao, Guang-Nian; Zhu, Xueyong; Li, Hongliang

    2015-08-01

    Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process. © 2015 American Heart Association, Inc.

  19. Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor α positive feedback loop in M2 macrophages.

    Science.gov (United States)

    Wang, Yi; Zhu, Jianghui; Zhang, Lei; Zhang, Zhijun; He, Long; Mou, Yong; Deng, Yanhan; Cao, Yong; Yang, Ping; Su, Yunchao; Zhao, Jianping; Zhang, Shu; Yu, Qilin; Hu, Jifa; Chen, Zhishui; Ning, Qin; Xiang, Xudong; Xu, Yongjian; Wang, Cong-Yi; Xiong, Weining

    2017-12-01

    C/EBP homologous protein (Chop), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during asthma development. However, its exact role in asthma pathogenesis is not fully understood. We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals. Studies were conducted in asthmatic patients and Chop-/- mice to dissect the role of Chop and ER stress in asthma pathogenesis. An ovalbumin (OVA)-induced allergic airway inflammation model was used to address the effect of Chop deficiency on asthma development. Next, the effect of Chop deficiency on macrophage polarization and related signaling pathways was investigated to demonstrate the underlying mechanisms. Asthmatic patients and mice after OVA induction exhibited aberrant Chop expression along with ER stress. Specifically, Chop was noted to be specifically overexpressed in macrophages, and mice deficient in Chop were protected from OVA-induced allergic airway inflammation, as manifested by attenuated airway inflammation, remodeling, and hyperresponsiveness. Chop was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an IL-4/signal transducer and activator of transcription 6/transcription factor EC (Tfec)/IL-4 receptor α positive feedback regulatory loop, in which IL-4 induces Chop expression, which then promotes signal transducer and activator of transcription 6 signaling to transcribe Tfec expression. Finally, Tfec transcribes IL-4 receptor α expression to promote M2 programming in macrophages. Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  20. Evaluating the potential bioactivity of a novel compound ER1626.

    Directory of Open Access Journals (Sweden)

    Lijun Wang

    Full Text Available ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626.MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and chicken embryos. The expression of estrogen receptor protein was investigated with western-blot analysis.ER1626 down-regulated the expression of estrogen receptor α protein and up-regulated β protein in MCF-7 and Ishikawa cells. The value of IC50 of ER1626 on MCF-7 and Ishikawa cells were respectively 8.52 and 3.08 µmol/L. Meanwhile, ER1626 decreased VEGF secretion of MCF-7 and Ishikawa cells, disturbed the formation of VEGF-stimulated tubular structure in HUVEC cells, and inhibited the angiogenesis on the chicken chorioallantoic membrane. Scratch assay revealed that ER1626 suppressed the migration of MCF-7, Ishikawa and HUVEC cells. In addition to induction tumor cell apoptosis, ER1626 arrested cell cycle in G1/G0 phase in MCF-7 cells and G2/M phase in Ishikawa cells.In conclusion, our results demonstrated that ER1626 has favorable bioactivities to be a potential candidate against breast cancer and angiogenesis.

  1. Purple perilla extracts allay ER stress in lipid-laden macrophages.

    Directory of Open Access Journals (Sweden)

    Sin-Hye Park

    Full Text Available There is a growing body of evidence that excess lipids, hypoxic stress and other inflammatory signals can stimulate endoplasmic reticulum (ER stress in metabolic diseases. However, the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. The current study investigated that 50 ng/ml oxidized LDL promoted unfolded protein response (UPR and ER stress in J774A1 murine macrophages, which was blocked by extracts (PPE of purple Perilla frutescens, a plant of the mint family Lamiaceae. The ER stressor tunicamycin was employed as a positive control. Treating 1-10 µg/ml oxidized LDL for 24 h elicited lipotoxic apoptosis in macrophages with obvious nuclear condensation and DNA fragmentation, which was inhibited by PPE. Tunicamycin and oxidized LDL activated and induced the UPR components of activating transcription factor 6 and ER resident chaperone BiP/Grp78 in temporal manners and such effects were blocked by ≥5 µg/ml PPE. In addition, PPE suppressed the enhanced mRNA transcription and splicing of X-box binding protein 1 (XBP1 by tunicamycin and oxidized LDL. The protein induction and nuclear translocation of XBP1 were deterred in PPE-treated macrophages under ER stress. The induction of ATP-binding cassette transporter A1 (ABCA1, scavenger receptor-B1 (SR-B1 and intracellular adhesion molecule-1 (ICAM-1 was abolished by the ER stressor in activated macrophages. The protein induction of ABCA1 and ICAM1 but not SR-B1 was retrieved by adding 10 µg/ml PPE to cells. These results demonstrate that PPE inhibited lipotoxic apoptosis and demoted the induction and activation of UPR components in macrophages. PPE restored normal proteostasis in activated macrophages oxidized LDL. Therefore, PPE was a potent agent antagonizing macrophage ER stress due to lipotoxic signals associated with atherosclerosis.

  2. MYC Protein-positive Diffuse Large B-Cell Lymphoma Features an Activated B-Cell Receptor Signal Pathway.

    Science.gov (United States)

    Wang, Wei-Ge; Jiang, Xiang-Nan; Liu, Ze-Bing; Zhou, Xiao-Yan; Li, Xiao-Qiu

    2017-04-01

    Components of the B-cell receptor (BCR) signaling pathway represent promising therapeutic targets in diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. MYC, a transcriptional factor and oncoprotein, is overexpressed in a fraction of DLBCL and indicates poor prognosis and aggressive clinical course when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, BCR signaling status in MYC-positive DLBCL cases and the potential efficacy of BCR signal inhibitors in treating this aggressive disease are unknown. To further elucidate the BCR signaling pathway in MYC-positive DLBCL, we analyzed the levels of BCR-associated genes according to MYC gene status, detected phosphorylated protein with primary DLBCL samples, and estimated the patient survival with MYC expression. In addition, we manipulated MYC gene expression and tested its effects on BCR signaling in vitro. We found that CD19, SYK, and BLK were highly expressed in DLBCL with MYC gene overexpression. MYC-positive DLBCL had higher levels of pSYK and pBLK, but only pSYK level correlated with patient survival. The in vitro studies demonstrated that overexpression of the MYC gene augmented BCR signaling, whereas MYC gene knockdown attenuated BCR signaling. Thus, MYC protein-positive DLBCL features highly activated BCR signaling and may represent a potential candidate for BCR inhibitor therapy.

  3. Positive Correlation between Androgen Receptor CAG Repeat Length and Metabolic Syndrome in a Korean Male Population

    Directory of Open Access Journals (Sweden)

    Jong Wook Kim

    2018-01-01

    Full Text Available Purpose: In epidemiological studies, there are various associations of androgen receptor (AR CAG with several diseases or phenotypes. However, the relationship between CAG repeat length and metabolic syndrome (MS remains unclear, especially in Asian populations. This study was designed to evaluate the relationship between AR CAG repeat length polymorphism and MS in a Korean male population. Materials and Methods: We explored the relationship between AR CAG repeat length polymorphism and MS in a Korean male population (n=337 from 2013 to 2014. AR CAG repeat were determined by microsatellite fragment sizing. Components of MS and laboratory data (lipid profile, fasting glucose, and glycated hemoglobin [HbA1c] were analyzed with AR CAG repeat length. Results: The mean AR CAG repeat length was 22.3±4.7. Sixty-nine men (20.5% were diagnosed with MS. Men with MS showed significantly longer AR CAG repeat lengths compared with men without MS (26.2 vs. 21.4, p<0.001. With increasing CAG repeat, the number of components meeting the NCEP criteria increased significantly. AR CAG repeat length was associated significantly with high density lipoprotein (HDL, triglyceride, and HbA1c levels. In the multivariate analysis, CAG repeat length, waist circumference, and levels of HDL were independently associated with MS. (odds ratio (OR=1.37, 1.19 and 0.90, p <0.001, 0.045, and 0.001, respectively. Conclusions: AR CAG repeat length was associated with MS and laboratory test results, such as those for HDL, triglycerides, and HbA1c, in Korean males. Longer CAG repeat length was identified as a risk factor for MS in Korean males.

  4. Positive Correlation between Androgen Receptor CAG Repeat Length and Metabolic Syndrome in a Korean Male Population.

    Science.gov (United States)

    Kim, Jong Wook; Bae, Young Dae; Ahn, Sun Tae; Kim, Jin Wook; Kim, Je Jong; Moon, Du Geon

    2018-01-01

    In epidemiological studies, there are various associations of androgen receptor (AR) CAG with several diseases or phenotypes. However, the relationship between CAG repeat length and metabolic syndrome (MS) remains unclear, especially in Asian populations. This study was designed to evaluate the relationship between AR CAG repeat length polymorphism and MS in a Korean male population. We explored the relationship between AR CAG repeat length polymorphism and MS in a Korean male population (n=337) from 2013 to 2014. AR CAG repeat were determined by microsatellite fragment sizing. Components of MS and laboratory data (lipid profile, fasting glucose, and glycated hemoglobin (HbA1c)) were analyzed with AR CAG repeat length. The mean AR CAG repeat length was 22.3±4.7. Sixty-nine men (20.5%) were diagnosed with MS. Men with MS showed significantly longer AR CAG repeat lengths compared with men without MS (26.2 vs. 21.4, p<0.001). With increasing CAG repeat, the number of components meeting the NCEP criteria increased significantly. AR CAG repeat length was associated significantly with high density lipoprotein (HDL), triglyceride, and HbA1c levels. In the multivariate analysis, CAG repeat length, waist circumference, and levels of HDL were independently associated with MS. (odds ratio (OR)=1.37, 1.19 and 0.90, p<0.001, 0.045, and 0.001, respectively). AR CAG repeat length was associated with MS and laboratory test results, such as those for HDL, triglycerides, and HbA1c, in Korean males. Longer CAG repeat length was identified as a risk factor for MS in Korean males.

  5. Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer.

    Science.gov (United States)

    André, Fabrice; Neven, Patrick; Marinsek, Nina; Zhang, Jie; Baladi, Jean-Francois; Degun, Ravi; Benelli, Giancarlo; Saletan, Stephen; Jerusalem, Guy

    2014-06-01

    International guidelines for hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2 negative (HER2(-)) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe. We conducted a retrospective chart review of 355 postmenopausal women with HR(+), HER2(-) advanced BC who progressed on ≥1 line of HT (adjuvant or advanced) and completed ≥1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy. Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease. Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR(+), HER2(-) advanced BC who responded to HT may not be achieved.

  6. Brief formalin fixation and rapid tissue processing do not affect the sensitivity of ER immunohistochemistry of breast core biopsies.

    Science.gov (United States)

    Sujoy, Victoria; Nadji, Mehrdad; Morales, Azorides R

    2014-04-01

    Recent studies have questioned the supporting evidence for the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines of the 8-hour minimum fixation time required for estrogen receptor immunohistochemistry (ER-IHC) assays in breast cancer. We investigated whether brief formalin fixation together with rapid tissue processing affects the sensitivity of ER in core breast biopsies. Five core samples each from 22 mastectomy specimens were collected and fixed in 10% formalin for periods ranging from 30 minutes to 1 week. Core 5 was fixed and processed according to the ASCO/CAP guidelines. ER-IHC was performed following heat-induced antigen retrieval using antibody 1D5. The proportion and intensity of reaction was recorded using the Q score. Five of 22 cancers were ER negative in all cores. In 17 ER-positive cases, no differences were found in the intensity of reaction between 30 minutes and 1 week of formalin fixation. Similarly, no difference was observed in the Q scores of rapidly and conventionally processed control tumor cores. Brief formalin fixation along with rapid processing has no negative effect on the sensitivity of ER-IHC in breast core biopsies. This combination significantly reduces the turnaround time for preparing breast needle biopsy specimens.

  7. Expression of androgen receptor and its association with estrogen receptor and androgen receptor downstream proteins in normal/benign breast luminal epithelium.

    Science.gov (United States)

    Wang, Xi; Yarid, Nicole; McMahon, Loralee; Yang, Qi; Hicks, David G

    2014-08-01

    The androgen receptor (AR) is strongly expressed in the majority of breast carcinomas, but its role in breast hormonal carcinogenesis is not clear. We believe a better knowledge of the biology of normal/benign breast tissue will be the key to understanding this process. Using standard immunohistochemical staining on consecutive sections and dual immunohistochemical labeling, we studied the expression pattern of AR and estrogen receptor (ER) in normal/benign breast luminal epithelial cells. We found that most of the AR-positive cells are also ER positive, about 10% of the cells are AR-positive only, whereas ER-positive only cells are uncommon, a distribution pattern of hormone receptor expression similar to what was revealed in invasive breast carcinomas. Whereas the expression of AR downstream proteins, such as prostate-specific antigen and gross cystic disease fluid protein, was either negative or unrelated to the AR status. We conclude that AR and ER expression status in invasive breast carcinomas reflects that of their progenitor cells in terminal duct lobular units. Our study did not reveal the expression of AR downstream proteins in normal/benign luminal epithelial cells at the regular immunohistochemistry level.

  8. Estrogen and progesterone receptor expression levels do not differ between lobular and ductal carcinoma in patients with hormone receptor-positive tumors

    NARCIS (Netherlands)

    Truin, Wilfred; Roumen, Rudi M.H.; Siesling, Sabine; van de Vijver, Koen K.; Tjan-Heijnen, Vivianne C.G.; Voogd, Adri C.

    Background Differences in estrogen (ER) and progesterone (PR) expression between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) could be an underlying reason for the difference in chemo-sensitivity and response to hormonal therapy between ILC and IDC. The aim of this study was

  9. Positive Charges on the Surface of Thaumatin Are Crucial for the Multi-Point Interaction with the Sweet Receptor

    Directory of Open Access Journals (Sweden)

    Tetsuya Masuda

    2018-02-01

    Full Text Available Thaumatin, an intensely sweet-tasting protein, elicits sweet taste with a threshold of only 50 nM. Previous studies from our laboratory suggested that the complex model between the T1R2-T1R3 sweet receptor and thaumatin depends critically on the complementarity of electrostatic potentials. In order to further validate this model, we focused on three lysine residues (Lys78, Lys106, and Lys137, which were expected to be part of the interaction sites. Three thaumatin mutants (K78A, K106A, and K137A were prepared and their threshold values of sweetness were examined. The results showed that the sweetness of K106A was reduced by about three times and those of K78A and K137A were reduced by about five times when compared to wild-type thaumatin. The three-dimensional structures of these mutants were also determined by X-ray crystallographic analyses at atomic resolutions. The overall structures of mutant proteins were similar to that of wild-type but the electrostatic potentials around the mutated sites became more negative. Since the three lysine residues are located in 20–40 Å apart each other on the surface of thaumatin molecule, these results suggest the positive charges on the surface of thaumatin play a crucial role in the interaction with the sweet receptor, and are consistent with a large surface is required for interaction with the sweet receptor, as proposed by the multipoint interaction model named wedge model.

  10. Hvor anvendelig er PKI?

    OpenAIRE

    Nielsen, Jon Magne

    2006-01-01

    Denne oppgaven ser på bruken av elektronisk ID i statlige etater i Norge i dag. Det ses spesielt på om bruken av tekologien PKI er en god løsning på etatenes behov på dette området. Som utgangspunkt for analysen er det sett spesielt på to statlige etater. Disse etatenes behov og bruk av elektronisk ID generelt og PKI spesielt blir undersøkt. Det er videre gjort rede for hvilke lover, forskrifter og andre førende dokumenter som danner de formelle rammebetingelsene for etaters bruk av PKI. ...

  11. Therapeutic effects of metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on phencyclidine-induced cognitive deficits in mice.

    Science.gov (United States)

    Horio, Mao; Fujita, Yuko; Hashimoto, Kenji

    2013-10-01

    This study was undertaken to examine the effects of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), a positive allosteric modulator (PAM) of metabotropic glutamate receptor 5 (mGlu₅), on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice were not improved by a single administration of CDPPB (10 mg/kg/day). However, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of CDPPB (10 mg/kg/day), but not of CDPPB (1.0 mg/kg/day). This study suggests that PCP-induced cognitive deficits in mice are improved by subsequent subchronic administration of CDPPB. Therefore, mGlu₅ PAMs would be potential therapeutic drugs for cognitive deficits in schizophrenia. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

  12. Positive emotional arousal increases duration of memory traces: different role of dopamine D1 receptor and β-adrenoceptor activation.

    Science.gov (United States)

    Conversi, D; Cruciani, F; Accoto, A; Cabib, S

    2014-07-01

    We investigated the effects of post-training administration of dopamine D1 receptor antagonist SCH 23390 and β-adrenergic receptor antagonist Propranolol on memory retention of an object sampled in a state of positive emotional arousal. Saline-treated mice trained and tested under high emotional/motivational arousal (High) showed discrimination of a novel object both 24 and 96 h post-training. Instead, mice trained and tested under low motivational arousal (Low) were unable to discriminate the novel object 96 h post-training. Both a high (2 mg/kg) and a low (1 mg/kg) dose of Propranolol reduced object discrimination in High mice tested 24 h post-training, whereas neither dose was effective in Low mice. A high dose of SCH 23390 (0.025 mg/kg) reduced discrimination of the novel object in High mice tested both 24 and 96 h post-training, whereas a low dose of the D1 antagonist (0.01 mg/kg) reduced discrimination in High mice tested 96 h post-training and abolished discrimination in Low mice tested 24h after training. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. MR and mammographic imaging features of HER2-positive breast cancers according to hormone receptor status: a retrospective comparative study.

    Science.gov (United States)

    Song, Sung Eun; Bae, Min Sun; Chang, Jung Min; Cho, Nariya; Ryu, Han Suk; Moon, Woo Kyung

    2017-07-01

    Background Human epidermal growth factor receptor 2-positive (HER2+) breast cancer has two distinct subtypes according to hormone receptor (HR) status. Survival, pattern of recurrence, and treatment response differ between HR-/HER2+ and HR+/HER2+ cancers. Purpose To investigate imaging and clinicopathologic features of HER2+ cancers and their correlation with HR expression. Material and Methods Between 2011 and 2013, 252 consecutive patients with 252 surgically confirmed HER2+ cancers (125 HR- and 127 HR+) were included. Two experienced breast radiologists blinded to the clinicopathologic findings reviewed the mammograms and magnetic resonance (MR) images using the BI-RADS lexicon. Tumor kinetic features were acquired by computer-aided detection (CAD). The imaging and clinicopathologic features of 125 HR-/HER2+ cancers were compared with those of 127 HR+/HER2+ cancers. Association between the HR status and each feature was assessed. Results Multiple logistic regression analysis showed that circumscribed mass margin (odds ratio [OR], 4.73; P HER2+ cancers. Between the two HER2+ subtypes, there were no differences in mammographic imaging presentations and calcification features and MR kinetic features by a CAD. Conclusion HER2+ breast cancers have different MR imaging (MRI) phenotypes and clinicopathologic feature according to HR status. MRI features related to HR and HER2 status have the potential to be used for the diagnosis and treatment decisions in HER2+ breast cancer patients.

  14. Increased number of IL-2, IL-2 receptor and IL-10 positive cells in premalignant lesions of the cervix.

    Science.gov (United States)

    Mindiola, Raimy; Caulejas, Diana; Núñez-Troconis, José; Araujo, Mary; Delgado, Mariela; Mosquera, Jesús

    2008-12-01

    Previous studies have shown the involvement of the immune response in the progression of human uterine cervix cancer. The aim of this study was to determine the expression of Interleukin-2 (IL-2), IL-2 receptor (IL-2R) and Interleukin 10 (IL-10) in different grades of cervical intraepithelial neoplasias of the exocervix (CIN 1, 2 and 3), and its relationship with the serum cytokine profiles and human papilomavirus (HPV) infection status. Indirect immunofluorescence was used to study the expression of IL-2, IL-2R and IL-10 in human cervical samples from 50 patients and 9 normal controls. Serum IL-2, IL-2R and IL-10 were measured by ELISA and HPV DNA and HPV types were identified by PCR. Increased number of IL-2, IL-2R and IL-10 positive cells were observed in the cervix from patients with CIN, associated with the grades of dysplasia. A significant correlation was observed between IL-2 and IL-2R (p>0.0001), IL-2 and IL-10 (p>0.0001), as well as IL-10 and IL-2R (p>0.0001). Twenty percent of patients were HPV positive and 84% of those patients were tissue cytokine positive. These results suggest that IL-2, IL-2R and IL-10 tissue expression may play a role in the development of cervical intraepithelial dysplasias.

  15. Challenges in the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer with brain metastases.

    Science.gov (United States)

    Liu, Minetta C; Cortés, Javier; O'Shaughnessy, Joyce

    2016-06-01

    Brain metastases are a major cause of morbidity and mortality for women with hormone receptor (HR)-positive breast cancer, yet little is known about the optimal treatment of brain disease in this group of patients. Although these patients are at lower risk for brain metastases relative to those with HER2-positive and triple-negative disease, they comprise the majority of women diagnosed with breast cancer. Surgery and radiation continue to have a role in the treatment of brain metastases, but there is a dearth of effective systemic therapies due to the poor penetrability of many systemic drugs across the blood-brain barrier (BBB). Additionally, patients with brain metastases have long been excluded from clinical trials, and few studies have been conducted to evaluate the safety and effectiveness of systemic therapies specifically for the treatment of HER2-negative breast cancer brain metastases. New approaches are on the horizon, such as nanoparticle-based cytotoxic drugs that have the potential to cross the BBB and provide clinically meaningful benefits to patients with this life-threatening consequence of HR-positive breast cancer.

  16. Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis

    DEFF Research Database (Denmark)

    Iankova, Irena; Petersen, Rasmus K; Annicotte, Jean-Sébastien

    2006-01-01

    Positive transcription elongation factor b (P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c...... with and phosphorylation of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master regulator of this process, on the promoter of PPARgamma target genes. PPARgamma-cdk9 interaction results in increased transcriptional activity of PPARgamma and therefore increased adipogenesis.......-Myc or MyoD. The P-TEFb complex is composed of a cyclin-dependent kinase (cdk9) subunit and a regulatory partner (cyclin T1, cyclin T2, or cyclin K). Because cdk9 has been shown to participate in differentiation processes, such as muscle cell differentiation, we studied a possible role of cdk9...

  17. Management of breast cancer brain metastases: Focus on human epidermal growth factor receptor 2-positive breast cancer.

    Science.gov (United States)

    Yuan, Peng; Gao, Song-Lin

    2017-03-25

    After the introduction of trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), the overall survival (OS) among patients with HER2-positive breast cancer has been substantially improved. However, among these patients, the incidence of brain metastases (BM) has been increasing and an increased proportion of them have died of intracranial progression, which makes HER2-positive breast cancer brain metastases (BCBM) a critical issue of concern. For local control of limited BM, stereotactic radiosurgery (SRS) and surgical resection are available modalities with different clinical indications. Postoperative or preoperative radiation is usually delivered in conjunction with surgical resection to boost local control. Adjuvant whole-brain radiotherapy (WBRT) should be deferred for limited BM because of its impairment of neurocognitive function while having no benefit for OS. Although WBRT is still the standard treatment for local control of diffuse BM, SRS is a promising treatment for diffuse BM as the technique continues to improve. Although large molecules have difficulty crossing the blood brain barrier, trastuzumab-containing regimens are critical for treating HER2-positive BCBM patients because they significantly prolong OS. Tyrosine kinase inhibitors are more capable of crossing into the brain and they have been shown to be beneficial for treating BM in HER2-positive patients, especially lapatinib combined with capecitabine. The antiangiogenic agent, bevacizumab, can be applied in the HER2-positive BCBM scenario as well. In this review, we also discuss several strategies for delivering drugs into the central nervous system and several microRNAs that have the potential to become biomarkers of BCBM.

  18. Photoaffinity labeling of pituitary GnRH receptors: significance of the position of photolabel on the ligand

    Energy Technology Data Exchange (ETDEWEB)

    Nikolics, K.; Szonyi, E.; Ramachandran, J.

    1988-03-08

    Photoreactive derivatives of GnRH and its analogues were prepared by incorporation of the 2-nitro-4(5)-azidophenylsulfenyl (2,4(5)-NAPS) group into amino acid residues at position 1, 3, 6, or 8 of the decapeptide sequence. The modification of Trp/sup 3/ by the 2,4-NAPS group led to a complete loss of the luteinizing hormone (LH) releasing as well as LH-release-inhibiting activity of the peptide. The (D-Lys(2,4-NAPS))/sup 6/ analog was a very potent agonist that, after covalent attachment by photoaffinity labeling, caused prolonged LH secretion at a submaximal rate. (Orn(2,4-NAPS))/sup 8/-GnRH, a full agonist with a relative potency of 7% of GnRH, after photoaffinity labeling caused prolonged maximal LH release from cultured pituitary cells. In contrast, (Orn(2,5-NAPS))/sup 8/-GnRH, although being equipotent with the 2,4-NAPS isomer in terms of LH releasing ability, was unable to cause prolonged LH release after photoaffinity labeling. Thus, (Orn(2,4-NAPS))/sup 8/GnRH is very effective photolabeling ligand of the functionally significant pituitary GnRH receptor. Based on this compound, a pituitary peptidase resistant derivative, D-Phe/sup 6/, (Orn(2,4-NAPS))/sup 8/-GnRH-(1-9)-ethylamide, was synthesized. This derivative showed high-affinity binding to pituitary membranes with a K/sub d/ comparable to those of other GnRH analogues. A radioiodinated form of this peptide was used for pituitary GnRH-receptor labeling. This derivative labeled 59- and 57-kDa proteins in rat and 58- and 56-kDa proteins in bovine pituitary membrane preparations, respectively. This peptide also labeled pituitary GnRH receptors in the solubilized state and therefore appears to be a suitable ligand for the isolation and further characterization of the receptor.

  19. Co-liposomes having anisamide tagged lipid and cholesteryl tryptophan trigger enhanced gene transfection in sigma receptor positive cells.

    Science.gov (United States)

    Misra, Santosh K; Moitra, Parikshit; Kondaiah, Paturu; Bhattacharya, Santanu

    2016-06-01

    Selective gene transfection could be strategy of interest for reducing off-target gene expression and toxicity. In this respect, sigma receptors are found to be over-expressed in many human tumors and liposomal formulations with ability to target these sigma receptors may improve the transfection efficiency to a significant level. To this direction, six novel lipids have been synthesized with different hydrophobic segments such as a long hydrophobic chain or a cholesteryl group and L-tryptophan as the head group. Three of them, Lipid 1, 3 and 5 possessed cationic Me3N(+) moiety at the distal end. In contrast each of the other three Lipid 2, 4 and 6 possessed sigma receptor targeting anisamide group with no cationic charge. Mixing of cationic and anisamide counterparts of the same lipid in a molar ratio of 1:1 produced co-liposomes L-M-1 (Lipid 1+2), L-M-2 (Lipid 3+4) and L-M-3 (Lipid 5+6). These co-liposomes, while keeping the sigma targeting anisamide tag intact, showed good DNA binding and release which were optimized from EB intercalation and gel electrophoresis assays. Inclusion of a zwitterionic, fusogenic natural lipid, DOPE, into the co-liposomes further improved the binding efficiencies of the lipid mixtures with DNA. These co-liposomes having cationic and anisamide lipids and DOPE were highly selective toward sigma positive HEK293 and HEK293T cells compared to the sigma negative HeLa cells. As evidenced from both FACS and luciferase assay, a lipid mixture comprising Lipid 3, 4 and DOPE in a molar ratio of 1:1:1 (L-M-2D1) was the best for transfection of reporter pEGFP-C3 and functional pCEP4-p53 gene plasmids. Anisamide mediated sigma receptor selectivity was further probed by pre-incubating the transfecting cells with lipids possessing anisamide and by quantification of the un-transfected plasmid DNA. Also each formulation was highly non-toxic in the cell lines examined. Copyright © 2016. Published by Elsevier B.V.

  20. 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.

  1. 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...... regions bound by both AHR and ER . Conventional and sequential ChIPs confirmed the recruitment of AHR and ER to many of the identified regions. Transcription factor binding site analysis revealed an overrepresentation of aryl hydrocarbon receptor response elements in regions bound by both AHR and ER...

  2. NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer.

    Science.gov (United States)

    Ma, Cynthia X; Gao, Feng; Luo, Jingqin; Northfelt, Donald W; Goetz, Matthew; Forero, Andres; Hoog, Jeremy; Naughton, Michael; Ademuyiwa, Foluso; Suresh, Rama; Anderson, Karen S; Margenthaler, Julie; Aft, Rebecca; Hobday, Timothy; Moynihan, Timothy; Gillanders, William; Cyr, Amy; Eberlein, Timothy J; Hieken, Tina; Krontiras, Helen; Guo, Zhanfang; Lee, Michelle V; Spies, Nicholas C; Skidmore, Zachary L; Griffith, Obi L; Griffith, Malachi; Thomas, Shana; Bumb, Caroline; Vij, Kiran; Bartlett, Cynthia Huang; Koehler, Maria; Al-Kateb, Hussam; Sanati, Souzan; Ellis, Matthew J

    2017-08-01

    Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER(+)) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies.Experimental Design: Eligible patients with clinical stage II/III ER(+)/HER2(-) breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%).Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression.Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055-65. ©2017 AACR. ©2017 American Association for Cancer Research.

  3. Correlation between tumour characteristics, SUV measurements, metabolic tumour volume, TLG and textural features assessed with {sup 18}F-FDG PET in a large cohort of oestrogen receptor-positive breast cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Lemarignier, Charles; Groheux, David [Saint-Louis Hospital, Assistance Publique - Hopitaux de Paris, Department of Nuclear Medicine, Paris (France); University Sorbonne Paris Cite, INSERM/CNRS UMR944/7212, Paris (France); Martineau, Antoine; Vercellino, Laetitia; Merlet, Pascal [Saint-Louis Hospital, Assistance Publique - Hopitaux de Paris, Department of Nuclear Medicine, Paris (France); Teixeira, Luis; Espie, Marc [Saint-Louis Hospital, Breast Diseases Unit, Paris (France); University Sorbonne Paris Cite, INSERM/CNRS UMR944/7212, Paris (France)

    2017-07-15

    The study was designed to evaluate 1) the relationship between PET image textural features (TFs) and SUVs, metabolic tumour volume (MTV), total lesion glycolysis (TLG) and tumour characteristics in a large prospective and homogenous cohort of oestrogen receptor-positive (ER+) breast cancer (BC) patients, and 2) the capability of those parameters to predict response to neoadjuvant chemotherapy (NAC). 171 consecutive patients with large or locally advanced ER+ BC without distant metastases underwent an {sup 18}F-FDG PET examination before NAC. The primary tumour was delineated with an adaptive threshold segmentation method. Parameters of volume, intensity and texture (entropy, homogeneity, contrast and energy) were measured and compared with tumour characteristics determined on pre-treatment breast biopsy (Wilcoxon rank-sum test). The correlation between PET-derived parameters was determined using Spearman's coefficient. The relationship between PET features and pathological findings was determined using the Wilcoxon rank-sum test. Spearman's coefficients between SUV{sub max} and TFs were 0.43, 0.24, -0.43 and -0.15 respectively for entropy, homogeneity, energy and contrast; they were higher between MTV and TFs: 0.99, 0.86, -0.99 and -0.87. All TFs showed a significant association with the histological type (IDC vs. ILC; 0.02 < P < 0.03) but didn't with immunohistochemical characteristics. SUV{sub max} and TLG predicted the pathological response (P = 0.0021 and P = 0.02 respectively); TFs didn't (P: 0.27, 0.19, 0.94, 0.19 respectively for entropy, homogeneity, energy and contrast). The correlation of TFs was poor with SUV parameters and high with MTV. TFs showed a significant association with the histological type. Finally, while SUV{sub max} and TLG were able to predict response to NAC, TFs failed. (orig.)

  4. Development of molecular imaging method for manitoring estrogen receptor activity

    Energy Technology Data Exchange (ETDEWEB)

    Jung, W. S.; Jung, J. G.; Kang, J. H.; Lee, Y. J.; Kim, K. I.; O, H. J.; Jung, J. M.; Lee, D. S.; Lee, M. C. [Seoul Nation University, Seoul (Korea, Republic of)

    2004-07-01

    Estrogen receptor is expressed in 50-60% of the breast cancer and hormone therapy is effective for only ER-positive breast cancer. Therefore, we need to know whether or not the ER is expressed in breast cancer before hormone therapy. So far, the method for monitoring ER positiveness in breast tissue is radioreceptor assay or immunohistochemistry which is invasive method due to tissue biopsy. In this study, we develop the molecular imaging method of sodium iodide symporter (NIS) gene as a reporter gene for monitoring ER activity. Because molecular imaging is evaluation method through the comparison between the image intensities obtained in vivo, molecular imaging method is noninvasive and easily quantitative. We constructed the recombinant plasmid (pERE-NIS) which NIS gene expression is controlled by estrogen response element (ERE) promoter. MCF-7, ER-expressing human breast cancer cell line, was transfected with pERE-NIS with lipofectamine (Invitrogen Co). When pERE-NIS transfected MCF-7 was treated with estradiol or tamoxifen, intracellular uptake of {sup 125}I was higher than those of non-treated. The activation of ERE by drug treatment was occurred and it was caused to expression of NIS gene. The degree of {sup 125}I uptake depend on treated drug concentration. However, in case of pERE-NIS transfected breast cancer which do not express ER, there was no response with drug treatment. Therefore, we can monitor ER functionality and the efficacy of drugs with this pERE-NIS reporter system.

  5. Metabolomics er fremtiden

    DEFF Research Database (Denmark)

    Pedersern, Birger

    2010-01-01

    Forskningen i fødevarer har fået et potent redskab i hånden. Metabolomics er vejen frem, mener professor Søren Balling Engelsen fra Københavns Universitet......Forskningen i fødevarer har fået et potent redskab i hånden. Metabolomics er vejen frem, mener professor Søren Balling Engelsen fra Københavns Universitet...

  6. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

    DEFF Research Database (Denmark)

    Thomsen, Karina G; Lyng, Maria B; Elias, Daniel

    2015-01-01

    Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers...... predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated...... by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p

  7. ER-positive breast cancer patients with more than three positive nodes or grade 3 tumors are at high risk of late recurrence after 5-year adjuvant endocrine therapy.

    Science.gov (United States)

    Song, Fangbin; Zhang, Jianbing; Li, Shanbao; Wu, Junyi; Jin, Tao; Qin, Jun; Wang, Ye; Wang, Min; Xu, Junming

    2017-01-01

    Currently, although several clinical trials available give strong suggestions that extension of endocrine therapy has benefits, the risk level at which patients may benefit from extended endocrine therapy remains uncertain. This study aimed to identify the proportion of patients at a substantial risk of late recurrence after 5-year adjuvant endocrine therapy. We reviewed 1,056 female patients with primary breast cancer who underwent curative resection between January 2006 and December 2011. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model to identify prognostic factors. A total of 327 eligible patients were eventually enrolled in this study. Among them, 42 (12.8%) patients suffered from distant metastasis and 34 (10.4%) patients experienced locoregional recurrence after 5-year adjuvant endocrine therapy. In multivariate analysis, patients with more than three positive nodes (hazard ratio [HR] =2.176, 95% CI=1.071-4.421; P =0.032) and histologic grade 3 disease (HR=2.098, 95% CI=1.300-3.385; P =0.002) were significantly associated with high risk of late recurrence. However, only histologic grade 3 (HR=2.212, 95% CI=1.166-4.194; P =0.015) was significantly associated with high risk of distant metastasis. Late relapse after completion of 5-year adjuvant endocrine therapy was still common, and grade 3 and more than three positive nodes were the risk factors of late recurrence, while grade 3 was the only risk factor of late distant metastasis. These patients might benefit from extended endocrine therapy.

  8. Reliability of core needle biopsy for determining ER and HER2 status in breast cancer

    NARCIS (Netherlands)

    Dekker, T. J. A.; Smit, V. T. H. B. M.; Hooijer, G. K. J.; van de Vijver, M. J.; Mesker, W. E.; Tollenaar, R. A. E. M.; Nortier, J. W. R.; Kroep, J. R.

    2013-01-01

    Several studies have assessed the concordance of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status between core needle biopsy (CNB) and resection specimens, usually in small patient series and with discordant results. ER and HER2 status determined on CNB and tissue

  9. KDEL Receptors Assist Dengue Virus Exit from the Endoplasmic Reticulum

    Directory of Open Access Journals (Sweden)

    Ming Yuan Li

    2015-03-01

    Full Text Available Membrane receptors at the surface of target cells are key host factors for virion entry; however, it is unknown whether trafficking and secretion of progeny virus requires host intracellular receptors. In this study, we demonstrate that dengue virus (DENV interacts with KDEL receptors (KDELR, which cycle between the ER and Golgi apparatus, for vesicular transport from ER to Golgi. Depletion of KDELR by siRNA reduced egress of both DENV progeny and recombinant subviral particles (RSPs. Coimmunoprecipitation of KDELR with dengue structural protein prM required three positively charged residues at the N terminus, whose mutation disrupted protein interaction and inhibited RSP transport from the ER to the Golgi. Finally, siRNA depletion of class II Arfs, which results in KDELR accumulation in the Golgi, phenocopied results obtained with mutagenized prME and KDELR knockdown. Our results have uncovered a function for KDELR as an internal receptor involved in DENV trafficking.

  10. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Casneuf T

    2016-02-01

    Full Text Available Tineke Casneuf,1 Amy E Axel,2 Peter King,2 John D Alvarez,2 Jillian L Werbeck,3 Tinne Verhulst,1 Karin Verstraeten,1 Brett M Hall,2 A Kate Sasser2 1Janssen Research and Development, Beerse, Belgium; 2Janssen Research and Development, Spring House, PA, 3LabConnect LLC, Seattle, WA, USAIntroduction: Interleukin-6 (IL-6 is an important growth factor for estrogen receptor-α (ERα-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis.Methods: The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ERα-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERa-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo.Results: In eight of nine ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway

  11. The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects

    OpenAIRE

    Kavvadias, Dominique; Sand, Philipp; Youdim, Kuresh A; Qaiser, M Zeeshan; Rice-Evans, Catherine; Baur, Roland; Sigel, Erwin; Rausch, Wolf-Dieter; Riederer, Peter; Schreier, Peter

    2004-01-01

    The functional characterization of hispidulin (4′,5,7-trihydroxy-6-methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity.After chemical synthesis, hispidulin was investigated at recombinant GABAA/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABA-induced chloride currents at tested receptor subtypes (α1−3,5,6β2γ2S) indicating positive allo...

  12. 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

  13. ER-positive breast cancer patients with more than three positive nodes or grade 3 tumors are at high risk of late recurrence after 5-year adjuvant endocrine therapy

    Directory of Open Access Journals (Sweden)

    Song F

    2017-10-01

    Full Text Available Fangbin Song,1 Jianbing Zhang,2 Shanbao Li,1 Junyi Wu,1 Tao Jin,1 Jun Qin,1 Ye Wang,1 Min Wang,1 Junming Xu1 1Department of General Surgery, 2Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China Purpose: Currently, although several clinical trials available give strong suggestions that extension of endocrine therapy has benefits, the risk level at which patients may benefit from extended endocrine therapy remains uncertain. This study aimed to identify the proportion of patients at a substantial risk of late recurrence after 5-year adjuvant endocrine therapy.Patients and methods: We reviewed 1,056 female patients with primary breast cancer who underwent curative resection between January 2006 and December 2011. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model to identify prognostic factors.Results: A total of 327 eligible patients were eventually enrolled in this study. Among them, 42 (12.8% patients suffered from distant metastasis and 34 (10.4% patients experienced locoregional recurrence after 5-year adjuvant endocrine therapy. In multivariate analysis, patients with more than three positive nodes (hazard ratio [HR] =2.176, 95% CI=1.071–4.421; P=0.032 and histologic grade 3 disease (HR=2.098, 95% CI=1.300–3.385; P=0.002 were significantly associated with high risk of late recurrence. However, only histologic grade 3 (HR=2.212, 95% CI=1.166–4.194; P=0.015 was significantly associated with high risk of distant metastasis.Conclusion: Late relapse after completion of 5-year adjuvant endocrine therapy was still common, and grade 3 and more than three positive nodes were the risk factors of late recurrence, while grade 3 was the only risk factor of late distant metastasis. These patients might benefit from extended endocrine therapy. Keywords: Ki-67, breast neoplasms, prognosis, extended endocrine

  14. 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

  15. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  16. Expression of Steroid Hormone Receptors of the Cervix in Cervical Intraepithelial Neoplasia Associated with Human Papillomavirus Infection in Infertile Women

    Directory of Open Access Journals (Sweden)

    E.O. Kindrativ

    2015-01-01

    When studying receptor status of cervical tissue in CIN, there are significant changes in the intensity of ER and PgR receptors expression. Immunohistochemical reaction in terms of identification of estrogen receptors is positive in 29.9 % of cases, negative — in 70.1 %. Positive PgR expression is set in 31.2 % of women with CIN, negative expression — in 68.8 %. In CIN and HPI, the redistribution of steroid receptors expression is marked, since ER is characterized by decrease of epithelial and appearance of stromal positive reaction. PgR expression differs by positive epithelial extinction with expressed nonspecific reaction in stromal component of the cervix. Estimation of hormone-receptor system of the cervix showed a significant decrease (p < 0.05 in ER volume content (twice in comparison with PgR (1.3 times. In CIN associated with HPI, a significant decrease in ER/PgR ratio is noted, with the lowest parameter in the group of patients with CIN-III (p < 0.05. Therefore, detection of the expression of steroid hormone receptors in cervical neoplasia associated with HPI in infertile women can be used as an additional criterion for determining the degree of dysplastic process in cervical epithelium.

  17. Human epidermal growth factor receptor 2-positive breast cancer: which cytotoxic agent best complements trastuzumab's efficacy in vitro?

    Directory of Open Access Journals (Sweden)

    Hurrell T

    2013-06-01

    Full Text Available Tracey Hurrell, Kim OuthoffDepartment of Pharmacology, University of Pretoria, Pretoria, South AfricaIntroduction: Despite trastuzumab having enhanced selectivity for human epidermal growth factor receptor 2 (HER-2 overexpressing breast cancer cells, treatment is hampered by interindividual variation and tumors with high mitogenic potential. The lack of significant clinical benefit in certain patient cohorts suggests that HER-2 expression is ineffective as a sole prognostic indicator of response to therapy. Therefore, optimizing the clinical role of trastuzumab in drug combinations remains critical for clinical success.Aim: To investigate the effects of trastuzumab in combination with either doxorubicin or geldanamycin on in vitro cell viability, cell cycling, apoptosis and relative HER-2 expression in HER-2-positive (SK-BR-3 and estrogen receptor-positive (MCF-7 breast adenocarcinoma models.Results: HER-2-rich SK-BR-3 cells demonstrated a greater sensitivity to the effects of doxorubicin than MCF-7 cells. Concurrent trastuzumab exposure resulted in a further reduction in cell viability. This decreased cell viability induced by doxorubicin was associated with activation of executioner caspases as well as with alterations in cell-cycle kinetics, primarily promoting S-phase accumulation. Doxorubicin had no effect on surface HER-2 density expression. Geldanamycin reduced cell viability significantly greater in SK-BR-3 than MCF-7 cells, and was associated with G2 cell-cycle accumulation. The addition of trastuzumab did not augment these effects. Geldanamycin promoted substantial reductions in relative surface HER-2 density in SK-BR-3 cells.Conclusion: The in vitro data supported the rationale for using doxorubicin in trastuzumab-based therapies. Therefore, despite the incidence of cardiotoxicity, doxorubicin could retain a fundamental role in treating HER-2-positive breast cancer. While geldanamycin is a potent cytotoxic agent, its concurrent use

  18. The prevalence of estrogen receptor-negative breast cancer in Ethiopia.

    Science.gov (United States)

    Kantelhardt, Eva Johanna; Mathewos, Assefa; Aynalem, Abreha; Wondemagegnehu, Tigeneh; Jemal, Ahmedin; Vetter, Martina; Knauf, Erdme; Reeler, Anne; Bogale, Solomon; Thomssen, Christoph; Stang, Andreas; Gemechu, Tufa; Trocchi, Pietro; Yonas, Bekuretsion

    2014-11-29

    In contrast with breast cancers (BCs) in other parts of the world, most previous studies reported that the majority of BCs in sub-Saharan Africa are estrogen-receptor (ER) negative. However, a recent study using the US SEER database showed that the proportion of ER-negative BC is comparable between US-born blacks and West-African born blacks but substantially lower in East African-born blacks, with over 74% of patients Ethiopians or Eritreans. In this paper, we provide the first report on the proportion of ER-negative BC in Ethiopia, and the relation to progesterone-receptor (PgR) status. We analysed 352 female patients with ER results available out of 1208 consecutive female BC patients treated at Addis Ababa-University Hospital, Ethiopia, from June 2005 through December 2010. The influences of age, stage, and histology on the probability of ER-negative tumours were assessed by a log-linear regression model. Of the 352 patients, only 35% were ER-negative. The proportion of ER-negative tumours decreased with advancing age at diagnosis and was not affected by histology or stage. For age, the proportion decreased by 6% for each additional 5 years (stage-adjusted prevalence ratio PR=0.94, 95% CI: 0.89-1.00). About 31% were ER- and PgR-negative, and 69% were ER- and/or PgR-positive. Contrary to most previous reports in other parts of sub-Saharan Africa, the majority of patients in Ethiopia are ER-positive rather than ER-negative. These findings are in line with low proportions of ER-negative BCs from East African immigrants within the SEER database, and they have clinical implications for management of BC patients in Ethiopia and other parts of sub-Saharan Africa where ER-status is not ascertained as part of routine management of the disease. Since the majority of patients showed ER-positive BC, Tamoxifen-therapy should be given to all patients even with unknown ER status.

  19. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

    DEFF Research Database (Denmark)

    Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki

    2017-01-01

    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9......,414 with breast cancer), all of European origin. We identified independent associations at P associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent...... associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA...

  20. Noradrenergic α₁ receptor antagonist treatment attenuates positive subjective effects of cocaine in humans: a randomized trial.

    Directory of Open Access Journals (Sweden)

    Thomas F Newton

    Full Text Available Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α(1 receptor antagonist doxazosin on the positive subjective effects of cocaine.Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind.Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of "high", "stimulated", "like cocaine", "desire cocaine", "any drug effect", and "likely to use cocaine if had access" (p<.001. Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of "stimulated", "like cocaine", and "likely to use cocaine if had access" (p<.05. There were trends for doxazosin to reduce ratings of "stimulated", "desire cocaine", and "likely to use cocaine if had access" (p<.10.Medications that block noradrenergic α₁ receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.Clinicaltrials.gov NCT01062945.

  1. Structure-based discovery of selective positive allosteric modulators of antagonists for the M2muscarinic acetylcholine receptor.

    Science.gov (United States)

    Korczynska, Magdalena; Clark, Mary J; Valant, Celine; Xu, Jun; Moo, Ee Von; Albold, Sabine; Weiss, Dahlia R; Torosyan, Hayarpi; Huang, Weijiao; Kruse, Andrew C; Lyda, Brent R; May, Lauren T; Baltos, Jo-Anne; Sexton, Patrick M; Kobilka, Brian K; Christopoulos, Arthur; Shoichet, Brian K; Sunahara, Roger K

    2018-02-16

    Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M 2 mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antagonist N -methyl scopolamine (NMS). Structure-based optimization led to compound '628, which enhanced binding of NMS, and the drug scopolamine itself, with a cooperativity factor (α) of 5.5 and a K B of 1.1 μM, while sparing the endogenous agonist acetylcholine. NMR spectral changes determined for methionine residues reflected changes in the allosteric network. Moreover, '628 slowed the dissociation rate of NMS from the M 2 mAChR by 50-fold, an effect not observed at the other four mAChR subtypes. The specific PAM effect of '628 on NMS antagonism was conserved in functional assays, including agonist stimulation of [ 35 S]GTPγS binding and ERK 1/2 phosphorylation. Importantly, the selective allostery between '628 and NMS was retained in membranes from adult rat hypothalamus and in neonatal rat cardiomyocytes, supporting the physiological relevance of this PAM/antagonist approach. This study supports the feasibility of discovering PAMs that confer subtype selectivity to antagonists; molecules like '628 can convert an armamentarium of potent but nonselective GPCR antagonist drugs into subtype-selective reagents, thus reducing their off-target effects. Copyright © 2018 the Author(s). Published by PNAS.

  2. Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.

    Science.gov (United States)

    Lai, Andiliy; Kahraman, Mehmet; Govek, Steven; Nagasawa, Johnny; Bonnefous, Celine; Julien, Jackie; Douglas, Karensa; Sensintaffar, John; Lu, Nhin; Lee, Kyoung-Jin; Aparicio, Anna; Kaufman, Josh; Qian, Jing; Shao, Gang; Prudente, Rene; Moon, Michael J; Joseph, James D; Darimont, Beatrice; Brigham, Daniel; Grillot, Kate; Heyman, Richard; Rix, Peter J; Hager, Jeffrey H; Smith, Nicholas D

    2015-06-25

    Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

  3. Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

    Science.gov (United States)

    Pareja, Fresia; Murray, Melissa P; Jean, Ryan Des; Konno, Fumiko; Friedlander, Maria; Lin, Oscar; Edelweiss, Marcia

    2017-01-01

    Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.

  4. ADX-47273, a mGlu5 receptor positive allosteric modulator, attenuates deficits in cognitive flexibility induced by withdrawal from 'binge-like' ethanol exposure in rats.

    Science.gov (United States)

    Marszalek-Grabska, Marta; Gibula-Bruzda, Ewa; Bodzon-Kulakowska, Anna; Suder, Piotr; Gawel, Kinga; Talarek, Sylwia; Listos, Joanna; Kedzierska, Ewa; Danysz, Wojciech; Kotlinska, Jolanta H

    2018-02-15

    Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl-d-aspartate (NMDA) receptors, and activation of one type results in the activation of the other. We examined whether (S)-(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl (ADX-47273), a positive allosteric modulator (PAM) of mGlu5 receptor, attenuates deficits in reversal learning induced by withdrawal (11-13days) from 'binge-like' ethanol input (5.0g/kg, i.g. for 5days) in the Barnes maze (a spatial learning) task in rats. We additionally examined the effects of ADX-47273 on the expression of the NMDA receptors subunit, GluN2B, in the hippocampus and prefrontal cortex, on the 13th day of ethanol withdrawal. Herein, withdrawal from repeated ethanol administration impaired reversal learning, but not the probe trial. Moreover, ADX-47273 (30mg/kg, i.p.) given prior to the first reversal learning trial for 3days in the Barnes maze, significantly enhanced performance in the ethanol-treated group. The 13th day of ethanol abstinence decreased the expression of the GluN2B subunit in the selected brain regions, but ADX-47273 administration increased it. In conclusion, positive allosteric modulation of mGlu5 receptors recovered spatial reversal learning impairment induced by withdrawal from 'binge-like' ethanol exposure. Such effect seems to be correlated with the mGlu5 receptors mediated potentiation of GluN2B-NMDA receptor mediated responses in the hippocampus and prefrontal cortex. Thus, our results emphasize the role of mGlu5 receptor PAM in the adaptive learning impaired by ethanol exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Jeg Er blevet FRANKofil

    DEFF Research Database (Denmark)

    Andersson, Lasse

    2014-01-01

    afhængig af Frank Underwood fra serien House of Cards på den fremadstormende TV-streamingstjenesten Netflix. Jeg har opdaget et nyt internetbaseret datingforhold. Et surrealt, fedt miks af det kyniske og joviale personificeret i karakteren Frank Underwood, som er helt igennem ubehagelig, men fantastisk...... spillet af Kevin Spacey. Og tak til Spacey der for en tid har forladt teateret ’The Old Vic’ i London for at begejstre mig. Der er generelt to årsager til mine FRANKofile tilbøjeligheder. For det første er Netflix’s remake af den tyve år gamle BBC serie House of Cards efter min menig et stykke tv...... anden grund, til at jeg er blevet Frankofil, er, at jeg ikke skal sidde og vente på næste søndag efter søndag efter søndag for at få lov at se næste afsnit. Netflix lagde alle tretten timer af sæson 2 ud på nettet. Jeg afgør selv, hvornår jeg skal have mere Frank! Men på trods af mit narkomanlignende...

  6. Innovation er brugerdreven!

    DEFF Research Database (Denmark)

    Helms, Niels Henrik

    2008-01-01

    Brugerdreven innovation er blevet svaret på mange af de udfordringer, som vores moderne samfund står overfor.Det er skrevet ind i såvel regeringsgrundlaget som i de forskellige tiltag, som skal ruste Danmark i forhold til globaliseringen. Vi har ifølge argumentationen her enrække særlige forudsæt......Brugerdreven innovation er blevet svaret på mange af de udfordringer, som vores moderne samfund står overfor.Det er skrevet ind i såvel regeringsgrundlaget som i de forskellige tiltag, som skal ruste Danmark i forhold til globaliseringen. Vi har ifølge argumentationen her enrække særlige...... forudsætninger: samspillet mellem virksomhederne, samspillet mellem forskning, virksomheder og fx erhvervspolitiske tiltag, den særlige danske designtradition. Samtidig er det netop innovationen og især den brugerdrevne innovation, som giver og isærdeleshed skal give Danmark en rolle i en globaliseret økonomi...

  7. Treatment Challenges and Survival Analysis of Human Epidermal Growth Factor Receptor 2-positive Breast Cancer in Real World.

    Science.gov (United States)

    Adusumilli, Praveen; Konatam, Meher Lakshmi; Gundeti, Sadashivudu; Bala, Stalin; Maddali, Lakshmi Srinivas

    2017-01-01

    Advent of trastuzumab has brought tremendous changes in the survival of human epidermal growth factor receptor 2 (Her2)-positive breast cancer patients. Despite the availability of the drug, it is still out of reach for many patients. There is very limited real world data regarding treatment challenges and survival analysis of these patients. Primary objective is disease-free survival (DFS) and secondary objective is overall survival (OS) and toxicity profile. Statistical analysis is done using GraphPad Prism 7.02. This is a retrospective study of all patients diagnosed with Her2-positive (Her2+) nonmetastatic invasive breast cancer from January 2007 to December 2013. In the period of this study, 885 patients are diagnosed with carcinoma breast, of which 212 are Her2/neu positive (23.9%). Of the 212 patients, only 76 (35.8%) patients received trastuzumab along with chemotherapy. Patients receiving trastuzumab with chemotherapy have longer 5-year DFS compared to those receiving chemotherapy alone, 92% and 52.6%, respectively (P = 0.0001). Five-year OS is 90.5% and 41.7% in those patients who received chemotherapy with and without trastuzumab, respectively (P = 0.0001). Seven patients (9.45%) developed Grade II reversible diastolic dysfunction. Grade II/III peripheral neuropathy due to paclitaxel is the main adverse effect seen in 21 patients. In spite of improvement in DFS and OS with trastuzumab, the number of patient receiving targeted therapy is very low due to financial constraints which need to be addressed to bridge the gap in survival of Her2+ patients.

  8. Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats.

    Science.gov (United States)

    Paterson, Neil E; Vlachou, Styliani; Guery, Sebastien; Kaupmann, Klemens; Froestl, Wolfgang; Markou, Athina

    2008-07-01

    Acute administration of gamma-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin self-administration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABA(B) receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABA(B) receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABA(B) receptor-positive modulator N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA(B) receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotine- and food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine self-administration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine self-administration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine- but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABA(B) receptor-positive modulators, similarly to GABA(B) receptor agonists, attenuated the reinforcing and reward

  9. Positive Modulation of GABAB Receptors Decreased Nicotine Self-administration and Counteracted Nicotine-induced Enhancement of Brain Reward Function in Rats

    Science.gov (United States)

    Paterson, Neil E.; Vlachou, Styliani; Guery, Sebastien; Kaupmann, Klemens; Froestl, Wolfgang; Markou, Athina

    2008-01-01

    Acute administration of γ-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin self-administration, and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABAB receptor positive modulators may represent potentially improved therapeutic compounds because of their fewer side-effects than receptor agonists. The present study investigated the effects of administration of the GABAB receptor positive modulators 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177), and co-administration of the GABAB receptor positive modulator N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABAB receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotine- and food-maintained responding under fixed-ratio 5 (FR5) and progressive-ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine self-administration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine self-administration, while co-administration of these compounds had additive effects. BHF177 administration selectively decreased nicotine-, but not food-, maintained responding under FR5 and progressive-ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABAB receptor positive modulators, similarly to GABAB receptor agonists, attenuated the reinforcing and reward

  10. Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer.

    Science.gov (United States)

    Lu, Janice

    2015-08-13

    Palbociclib was approved by the FDA for use in combination with letrozole for the treatment of postmenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. In addition, the combination of palbociclib with fulvestrant resulted in superior outcome than fulvestrant alone in those who had progressed during prior endocrine therapy. This research highlight summarized the current development of CDK4/CDK6 inhibitors and future directions in the treatment of advanced hormone-receptor-positive breast cancer.

  11. Maximum growth and survival of estrogen receptor-alpha positive breast cancer cells requires the Sin3A transcriptional repressor

    Directory of Open Access Journals (Sweden)

    Alarid Elaine T

    2010-09-01

    Full Text Available Abstract Background Sin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex. It functions as a scaffold upon which proteins with enzymatic activity dock, including chromatin modifying histone deacetylases. Although regulation of transcription by Sin3A has been studied in detail, little is understood about the function of Sin3A in cancer cells. We previously showed that Sin3A is expressed in breast cancer cells and is a repressor of estrogen receptor-alpha (ERα, ESR1 gene expression. Here, we expand our previous studies to elucidate the function of Sin3A in the control of gene expression and growth of breast cancer cells. Results Analysis of gene expression following knockdown of Sin3A revealed changes in both basal and regulated gene transcription. Genes of known importance in breast cancer and estrogen signaling, including ERBB2, PGR, MYC, CLU, and NCOA2, were among those identified as Sin3A-responsive. The mechanism of Sin3A action varied among genes and was found to be mediated through both HDAC1/2 -dependent and -independent activities. Loss of Sin3A inhibited breast cancer cell growth by increasing apoptosis without affecting cell cycle progression. Analysis of both ERα-positive and ERα-negative cell lines revealed that the effects of Sin3A on growth were cell-type specific, as Sin3A expression promoted maximum growth of only the ERα-positive cells, and, notably, Sin3A protein itself was increased by estrogen. Further gene expression experiments revealed that Sin3A repressed expression of key apoptotic genes, including TRAIL, TRAILR1, CASP10, and APAF1, in ERα-positive, but not ERα-negative, cell lines, which could provide a mechanistic explanation for cell-type differences in growth. Conclusions This study identifies Sin3A as a regulator of gene expression, survival, and growth in ERα-positive breast cancer cells. Sin3A regulates the

  12. Risk of second breast cancer according to estrogen receptor status and family history.

    Science.gov (United States)

    Bouchardy, Christine; Benhamou, Simone; Fioretta, Gérald; Verkooijen, Helena M; Chappuis, Pierre O; Neyroud-Caspar, Isabelle; Castiglione, Monica; Vinh-Hung, Vincent; Vlastos, Georges; Rapiti, Elisabetta

    2011-05-01

    A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48-0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19-3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81-14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57-21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58-118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.

  13. Tale er guld

    DEFF Research Database (Denmark)

    Juel Henrichsen, Peter

    2014-01-01

    Mange danske kommuner er parate til at indfase automatisk talegenkendelse, men er samtidig nervøse efter en lang række dårlige businesscases i den nærmere fortid. Der klages over høje licenspriser og lavt serviceniveau, den typiske virkning af et de facto monopol på leverandørsiden. Denne artikel...... området - som vi håber at se i 2014 - en begivenhed som præcis kunne løsne den nuværende deadlock og åbne et milliardstort marked for taleteknologi i det offentliges tjeneste....

  14. Bioenergi er blevet moderne

    DEFF Research Database (Denmark)

    Sønderberg Petersen, L.

    2003-01-01

    Risø har udgivet en rapport om moderne bioenergi. Den slår fast, at biomasse er en ligeså værdifuld ressource som vind, og at Danmark vil kunne spille en væsentlig rolle i udviklingen af den teknologi, der skal til for at udnytte hele dens potentiale.......Risø har udgivet en rapport om moderne bioenergi. Den slår fast, at biomasse er en ligeså værdifuld ressource som vind, og at Danmark vil kunne spille en væsentlig rolle i udviklingen af den teknologi, der skal til for at udnytte hele dens potentiale....

  15. Androgen receptor signaling pathways as a target for breast cancer treatment.

    Science.gov (United States)

    Pietri, Elisabetta; Conteduca, Vincenza; Andreis, Daniele; Massa, Ilaria; Melegari, Elisabetta; Sarti, Samanta; Cecconetto, Lorenzo; Schirone, Alessio; Bravaccini, Sara; Serra, Patrizia; Fedeli, Anna; Maltoni, Roberta; Amadori, Dino; De Giorgi, Ugo; Rocca, Andrea

    2016-10-01

    The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors. © 2016 Society for Endocrinology.

  16. ER? suppresses slug expression directly by transcriptional repression

    OpenAIRE

    Ye, Yin; Xiao, Yi; Wang, Wenting; Yearsley, Kurtis; Gao, Jian-Xin; Barsky, Sanford H.

    2008-01-01

    Two of the most common signalling pathways in breast cancer are the ER (oestrogen receptor) ligand activation pathway and the E-cadherin snai1 slug EMT (epithelial?mesenchymal transition) pathway. Although these pathways have been thought to interact indirectly, the present study is the first to observe direct interactions between these pathways that involves the regulation of slug expression. Specifically we report that ligand-activated ER? suppressed slug expression directly by repression o...

  17. Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling.

    Science.gov (United States)

    Lee, Jae Youn; Lee, Hyun Jung; Lee, Eun Jung; Jang, Sung Hee; Kim, Hyeyoung; Yoon, Joo-Heon; Chung, Kwang Chul

    2009-12-01

    The Down syndrome candidate region-1 gene (DSCR1, also known as RCAN1) is situated close to the Down Syndrome Critical Region (DSCR), which contains genes responsible for many features of Down syndrome. DSCR1 modulates calcineurin phosphatase activity, though its functional role is incompletely understood. Here we investigated the role of DSCR1-1S isoform in IL-1 receptor (IL-1R)-mediated signaling by analyzing interaction between DSCR1-1S and the IL-1R pathway components Tollip, IRAK-1, and TRAF6. Co-immunoprecipitation analyses of HEK293 cells revealed that DSCR1-1S interacted with Tollip, an IRAK-1 inhibitor, leading to the dissociation of IRAK-1 from Tollip. Similarly, both DSCR1-1S and Tollip interacted with TRAF6, with DSCR1 reducing interaction between Tollip and TRAF6. DSCR1-1S also stimulated IL-1R-mediated signaling pathways, TAK1 activation, NF-kappaB transactivation, and IL-8 production, all downstream consequences of IL-1R activation. Together, these results suggest that DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation.

  18. 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.

  19. Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

    Science.gov (United States)

    POYET, CÉDRIC; HERMANNS, THOMAS; ZHONG, QING; DRESCHER, EVA; EBERLI, DANIEL; BURGER, MAXIMILIAN; HOFSTAEDTER, FERDINAND; HARTMANN, ARNDT; STÖHR, ROBERT; ZWARTHOFF, ELLEN C.; SULSER, TULLIO; WILD, PETER J.

    2015-01-01

    In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (PFGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis. PMID:26722237

  20. Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid.

    Directory of Open Access Journals (Sweden)

    Enrico D'Aniello

    Full Text Available Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor αb1 (RARαb1, a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARαb2 or concurrent depletion of RARαb1 and RARαb2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARαb1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA.

  1. Membranous nephropathy associated with pregnancy: an anti-phospholipase A2 receptor antibody-positive case report.

    Science.gov (United States)

    Uchino, Eiichiro; Takada, Daisuke; Mogami, Haruta; Matsubara, Takeshi; Tsukamoto, Tatsuo; Yanagita, Motoko

    2018-01-18

    Pregnancy and membranous nephropathy (MN) can occur concurrently with nephrotic syndrome. However, the pathophysiology of MN associated with pregnancy remains unclear, including the involvement of anti-M-type phospholipase A2 receptor (PLA2R) antibody, the major antigen of idiopathic MN (iMN). A treatment for the condition is also not established. We present the case of a 43-year-old pregnant female with incidental proteinuria and hypoalbuminemia. We made a diagnosis of nephrotic syndrome at 11 week gestation. Renal biopsy revealed iMN using predominant granular staining of IgG4 along the glomerular basement membrane. No secondary cause was identified. Oral glucocorticoid therapy was started from 17 week gestation and induced complete remission at 28 week gestation. A healthy infant was born at 38 week gestation. Glucocorticoid therapy was stopped postpartum without MN relapse. Anti-PLA2R antibody was later found to be positive using serum reserved from before treatment. In conclusion, we presented the case of a pregnant woman with iMN and anti-PLA2R antibodies, whose nephrotic syndrome was successfully controlled with oral glucocorticoids to reach complete remission, even after tapering off the medication. Pregnancy per se might be associated with iMN onset.

  2. Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.

    Science.gov (United States)

    Giltnane, Jennifer M; Hutchinson, Katherine E; Stricker, Thomas P; Formisano, Luigi; Young, Christian D; Estrada, Monica V; Nixon, Mellissa J; Du, Liping; Sanchez, Violeta; Ericsson, Paula Gonzalez; Kuba, Maria G; Sanders, Melinda E; Mu, Xinmeng J; Van Allen, Eliezer M; Wagle, Nikhil; Mayer, Ingrid A; Abramson, Vandana; Gόmez, Henry; Rizzo, Monica; Toy, Weiyi; Chandarlapaty, Sarat; Mayer, Erica L; Christiansen, Jason; Murphy, Danielle; Fitzgerald, Kerry; Wang, Kai; Ross, Jeffrey S; Miller, Vincent A; Stephens, Phillip J; Yelensky, Roman; Garraway, Levi; Shyr, Yu; Meszoely, Ingrid; Balko, Justin M; Arteaga, Carlos L

    2017-08-09

    Inhibition of proliferation in estrogen receptor-positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/human epidermal growth factor receptor 2-negative (HER2-) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  3. Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender

    DEFF Research Database (Denmark)

    Glenthoj, Birte Y; Mackeprang, Torben; Svarer, Claus

    2006-01-01

    with single-photon emission computerized tomography (SPECT) using the D(2/3)-receptor ligand [123I]epidepride. RESULTS: In the hitherto largest study on extrastriatal D(2/3) receptors we detected a significant correlation between frontal D(2/3) BP values and positive schizophrenic symptoms in the larger group...... of male schizophrenic patients, higher frontal BP values in male (n = 17) compared to female (n = 8) patients, and - in accordance with this - significantly fewer positive schizophrenic symptoms in the female patients. No significant differences in BP values were observed between patients and controls......; the patients, however, had significantly higher BP in the right compared to the left thalamus, whereas no significant hemispheric imbalances were observed in the healthy subjects. CONCLUSIONS: The present data are the first to confirm a significant correlation between frontal D(2/3) receptor BP values...

  4. Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis.

    Science.gov (United States)

    Nakata, R; Motomura, M; Masuda, T; Shiraishi, H; Tokuda, M; Fukuda, T; Ando, T; Yoshimura, T; Tsujihata, M; Kawakami, A

    2013-09-01

    The differences in the characteristics of thymus histology, coexisting autoimmune diseases and related autoantibodies between anti-muscle-specific receptor tyrosine kinase (MuSK)-antibody (Ab)-positive myasthenia gravis (MG) patients, and anti-acetylcholine receptor (AChR)-Ab-positive MG patients are not clearly defined. The types of thymus histology, coexisting autoimmune diseases and associated Abs in 83 MuSK-Ab-positive patients nationwide were investigated and were compared with those in AChR-Ab-positive patients followed at our institute (n = 83). As for the autoantibodies associated with thymoma, titin Abs were measured. Thymoma was not present in any of the MuSK-Ab-positive patients but presented in 21 patients (25.3%) amongst the AChR-Ab-positive patients. Titin Abs were absent in MuSK-Ab-positive patients but positive in 25 (30.1%) of the AChR-Ab-positive patients. Concomitant autoimmune diseases were present in eight MuSK-Ab-positive patients (9.6%) amongst whom Hashimoto's thyroiditis and rheumatoid arthritis predominated, whereas 22 AChR-Ab-positive patients (26.5%) had one or more concomitant autoimmune diseases of which Graves' disease predominated. Differences in frequency of thymoma and thymic hyperplasia, coexisting autoimmune diseases and autoantibody positivity between MuSK-Ab-positive and AChR-Ab-positive MG were indicated, suggesting that, in contrast with AChR-Ab-positive MG, thymus does not seem to be involved in the pathogenic mechanisms of MuSK-Ab-positive MG. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

  5. Extra virgin olive oil potentiates the effects of aromatase inhibitors via glutathione depletion in estrogen receptor-positive human breast cancer (MCF-7) cells.

    Science.gov (United States)

    Ismail, Amar Mohamed; In, Lionel L A; Tasyriq, Mohammad; Syamsir, Devi Rosmy; Awang, Khalijah; Mustafa, Ayda Hussein Omer; Idris, Omer Fadul; Fadl-Elmula, Imad; Hasima, Noor

    2013-12-01

    There have been numerous evidences supporting the relationship between olive oil and cancer, with most of the attention being directed toward its fat and phenolic content. The aims of this study were to investigate whether EVOO and OA could enhance the effects of aromatase inhibitors (letrozole and anastrozole) in ER-positive MCF-7 cells, as well as to investigate its influence on cytochrome c release and GSH levels. It was observed that upon combination treatment, anti-proliferation effects and apoptosis induction were augmented. Apoptosis was triggered via the intrinsic pathway in accordance with cytochrome c release into the cytosol based on IF-IC and ELISA observations. Intracellular GSH levels were also reduced upon EVOO/OA treatment in combination with aromatase inhibitors, and were found to be inversely correlated to cytosolic cytochrome c levels. Additionally, the estrogenic suppressive effects of letrozole and anastrozole were amplified when used in combination with EVOO/OA. Therefore, the employment of aromatase inhibitors in combination with EVOO/OA could orchestrate a reduction in intracellular estrone biosynthesis which feeds ER-positive cells, while simultaneously depleting GSH levels and increasing ROS generation, thus releasing cytochrome c and subsequent induction of apoptosis in MCF-7 cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Ondskaben er fortryllende

    DEFF Research Database (Denmark)

    Schubart, Rikke

    2013-01-01

    Indlæg om tv-serien Once Upon a Time (2011-), der hører til genren fairytale fantasy, der blander eventyr og fantasy. Her bliver alle eventyr brugt i en fortælling om alle beboere i en lille by, der ikke ved, at de i virkeligheden er eventyr-karakterer....

  7. Riget - alt er tilladt

    DEFF Research Database (Denmark)

    Agger, Gunhild

    2017-01-01

    Riget indtager en nøglestilling, når overgangen mellem faser i Triers produktion skal karakteriseres. Riget danner bro mellem den billedfascination og de radikale stileksperimenter, der præger Triers tidlige produktion, og den genre- og plotbevidsthed, der er typisk for film som Breaking the Wave...... (1996) og Dancer in the Dark (2000). Artiklen analyserer hvordan....

  8. It er godt - basta!

    DEFF Research Database (Denmark)

    Bundsgaard, Jeppe

    2012-01-01

    Der er offentlig konsensus om at it i undervisningen fører til øget faglighed. Men it kan lige så godt resultere i ringere undervisning som i bedre - og ofte anvendes it helt traditionelt og fantasiløst....

  9. Hvad er tidligt sprog

    DEFF Research Database (Denmark)

    Skriver Jensen, Anders

    2009-01-01

    Forfatteren argumenterer for at "early literacy" kan oversættes til "tidligt sprog"; særligt når der er tale om en helhedsorienteret tilgang med vægt på sprog som et alsidigt medie for kommunikation- og betydningsskabelse. Med inspiration fra Jerome Bruners kulturpsykologi diskuteres mulige...

  10. Litteratur er nyttig

    DEFF Research Database (Denmark)

    Kaspersen, Peter

    2012-01-01

    Den anmeldte bog er en forskningsbaseret debatbog om hvilken nytteværdi litteratur har. Bogen placeres i sammenhæng med en række bøger på nordiske sprog og engelsk om litteraturens, litteraturundervisningens og -forskningens legitimitet. Argumentatioen i bogen bygger på Bakhtins litteratursyn, og...

  11. Ideologi er noget bras

    DEFF Research Database (Denmark)

    Hansen, Brian Benjamin; Jøker Bjerre, Henrik

    fra den slovenske filosof Slavoj Zizek stilles imidlertid det spørgsmål i bogen, om ideologien idag ikke blot har taget en anden form. Vi lever i dag ikke i post-ideologiske tider. Snarere er braset selv – X Factor, forbrugsobjekter, underholdning, følelser og balloner – blevet den næsten usynlige...

  12. er 1999

    DEFF Research Database (Denmark)

    Jensen, J. P.; Søndergaard, M.; Jeppesen, E.

    land bidrager med flest næringsstoffer til søerne Stoftilførslen af såvel fosfor som kvælstof til søerne har i 1999 som tidligere år været domineret af tilførslen fra det åbne land, der gen-nemsnitligt har bidraget med ca. 73 % af fosfortilførslen og ca. 78 % af kvælstoftilførslen (Fig. 0...... for de mest belastede søer. Således er både fosfor- og kvælstof-bidraget fra byspildevand og industrispildevand fra 1989 til 1999 reduceret meget markant fra ca. 22 % til ca. 3 %. Figur 0.1 Kildefordeling for fosfor- og kvælsstoftilførslen til søerne i 1999. Grå: Åbent land (landbrug + baggrund). Sort...... af overvågningssøerne, efter at søer-ne er blevet klarvandede som følge af ændringer i fiskebestanden. I halvdelen af søerne var kvælstof-tilbageholdelsen i 1999 højere end 26 %. Medianen og gennemsnittet for den absolutte kvælstoftilbagehol-delse var 93 og 111 mg N m-2 dag-1 svarende til 340 og 405...

  13. Hvad er alternativet?

    DEFF Research Database (Denmark)

    Jensen, Niels Rosendal

    2015-01-01

    Anmeldelsen af Mårtenssons "Konkurrencestatens pædagogik" præsenterer dels forfatterens kritik af og alternativ til den igangværende reform af folkeskolen, dels advarer den mod at forfalde til konspirationsteori. Endelig peger den på, at Mårtenssons såkaldte alternativ er gammel vin på nye flaske...

  14. Patienten - hvor er patienten?

    DEFF Research Database (Denmark)

    Nielsen, Gitte; Dau, Susanne

    2011-01-01

    på, hvad der historisk og nutidigt karakteriserer teori og praksis, samt forholdet herimellem. I den empiriske del er der, med udgangspunkt i Gadamers hermeneutiske tilgang, foretaget tre kvalitative forkusgruppeinterview. Ét af sygeplejestuderende, ét af kliniske vejledere og ét af undervisere...

  15. Er danskerne racister?

    DEFF Research Database (Denmark)

    Necef, Mehmet Ümit; Bech, Henning

    Igennem de seneste årtier er det blevet almindeligt at tale om, at der er en udbredt racisme i Danmark. Påstande om danskernes racisme, fremmedhad og diskrimination optræder dagligt i offentligheden og i medierne, og der henvises ofte til, hvad ’forskerne’ og de ’videnskabelige undersøgelser’ siger...... om emnet. Der kan da næppe heller være tvivl om, at der forekommer racistiske holdninger hos nogle danskere. Men er problemet så stort, som det gøres til i den offentlige debat? Bogen ønsker at afklare, hvorvidt der er videnskabelig dokumentation for påstandene om danskernes racisme. Den går i dybden...... med en række forskeres og eksperters udtalelser på området og præsenterer en grundig analyse af deres fremstilling af dansk racisme i forhold til emner som kultur, seksualitet, kriminalitet og arbejdsmarked....

  16. Nordslesvigeren er nr. 1

    DEFF Research Database (Denmark)

    Christensen, Steffen Lind

    2015-01-01

    Historien om de nordslesvigske krigsdeltagere under 1. Verdenskrig er traditionelt blevet behandlet i et nationalt perspektiv. Her benævnes soldaterne oftest som ’danske’. Denne artikel undersøger, hvordan nordslesvigske soldater på Østfronten selv udtrykte deres identitet i krigssituationen...

  17. 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.

  18. Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.

    Science.gov (United States)

    Ma, Gang; He, Jianjun; Yu, Yang; Xu, Yixiang; Yu, Xiaobin; Martinez, Jarrod; Lonard, David M; Xu, Jianming

    2015-01-01

    Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers.

  19. 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

    2017-01-01

    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...

  20. Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors

    NARCIS (Netherlands)

    Kasheverov, I.E.; Zhmak, M.N.; Vulfius, C.A.; Corbacheva, E.V.; Mordvintsev, D.Y.; Utkin, Y.N.; van Elk, R.; Smit, A.B.; Tsetlin, V.I.

    2006-01-01

    α-Conotoxins from Conus snails are indispensable tools for distinguishing various subtypes of nicotinic acetylcholine receptors (nAChRs), and synthesis of α-conotoxin analogs may yield novel antagonists of higher potency and selectivity. We incorporated additional positive charges into α-conotoxins

  1. Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer

    DEFF Research Database (Denmark)

    Sonnenblick, Amir; Agbor-Tarh, Dominique; Bradbury, Ian

    2017-01-01

    Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the cont...

  2. MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer

    Science.gov (United States)

    Lowery, Aoife J; Miller, Nicola; Devaney, Amanda; McNeill, Roisin E; Davoren, Pamela A; Lemetre, Christophe; Benes, Vladimir; Schmidt, Sabine; Blake, Jonathon; Ball, Graham; Kerin, Michael J

    2009-01-01

    Introduction Breast cancer is a heterogeneous disease encompassing a number of phenotypically diverse tumours. Expression levels of the oestrogen, progesterone and HER2/neu receptors which characterize clinically distinct breast tumours have been shown to change during disease progression and in response to systemic therapies. Mi(cro)RNAs play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as regulators of tumour behaviour and progression. The aims of this study were to identify miRNA signatures that accurately predict the oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor status of breast cancer patients to provide insight into the regulation of breast cancer phenotypes and progression. Methods Expression profiling of 453 miRNAs was performed in 29 early-stage breast cancer specimens. miRNA signatures associated with ER, PR and HER2/neu status were generated using artificial neural networks (ANN), and expression of specific miRNAs was validated using RQ-PCR. Results Stepwise ANN analysis identified predictive miRNA signatures corresponding with oestrogen (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. MiR-342 and miR-520g expression was further analysed in 95 breast tumours. MiR-342 expression was highest in ER and HER2/neu-positive luminal B tumours and lowest in triple-negative tumours. MiR-520g expression was elevated in ER and PR-negative tumours. Conclusions This study demonstrates that ANN analysis reliably identifies biologically relevant miRNAs associated with specific breast cancer phenotypes. The association of specific miRNAs with ER, PR and HER2/neu status indicates a role for these miRNAs in disease classification of breast cancer. Decreased expression of miR-342 in the

  3. Stabilized (111)in-labeled sCCK8 analogues for targeting CCK2-receptor positive tumors: synthesis and evaluation.

    NARCIS (Netherlands)

    Roosenburg, S.; Laverman, P.; Joosten, L.; Eek, A.; Oyen, W.J.G.; Jong, M. de; Rutjes, F.P.J.T.; Delft, F.L. van; Boerman, O.C.

    2010-01-01

    Radiolabeled cholecystokinin-8 (CCK8) peptide analogues can be used for peptide receptor radionuclide imaging and therapy for tumors expressing CCK2/gastrin receptors. Earlier findings indicated that sulfated CCK8 (sCCK8, Asp-Tyr(OSO(3)H)-Met-Gly-Trp-Met-Asp-Phe-NH(2)) may have better

  4. In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate

    Science.gov (United States)

    Groman, Stephanie M.; James, Alex S.; Seu, Emanuele; Tran, Steven; Clark, Taylor A.; Harpster, Sandra N.; Crawford, Maverick; Burtner, Joanna Lee; Feiler, Karen; Roth, Robert H.; Elsworth, John D.; London, Edythe D.

    2014-01-01

    For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. PMID:25339755

  5. Survival of women with ovarian carcinomas and borderline tumors is not affected by estrogen and progesterone receptor status.

    Science.gov (United States)

    Sallum, Luis Felipe; Sarian, Luis Otavio; Lucci De Angelo Andrade, Liliana; Vassallo, José; Soares, Fernando Augusto; Pinto, Glauce Aparecida; Ferreira, Patrícia Andréia; Derchain, Sophie

    2013-04-01

    To examine the patterns of estrogen receptor (ER) and progesterone receptor (PR) expression in borderline ovarian tumors (BOTs) and ovarian carcinomas. We also assessed the disease-free survival (DFS) and overall survival (OS) in women with ovarian carcinoma, in relation to ER and/or PR expression. We examined ER/PR expression in 38 BOTs and 172 ovarian carcinomas removed from patients treated at the State University of Campinas-UNICAMP (Brazil), from 1993 to 2008 and followed for up to 60 months using tissue microarray-based immunohistochemistry. Twenty-eight (73.7%) mucinous and 10 (26.3%) serous BOTs were included. Ovarian carcinomas consisted mainly of 79 (46.0%) serous, 44 (25.5%) mucinous, 17 (9.8%) endometrioid, 10 (5.8%) clear-cell types. There was no significant difference of the ER/PR expression between BOT and ovarian carcinoma (p=0.55 for ER alone, 0.90 for PR alone, and 0.12 for combined expression). The level of ER/PR expression in BOTs was significantly higher in serous than in mucinous tumors (p<0.01). In carcinomas, ER/PR was higher in serous tumors than in mucinous (p<0.01) and clear cell tumors (p=0.02), and higher in endometrioid tumors than in mucinous tumors (p<0.01). DFS was affected neither by the clinical characteristics nor by combined steroid receptor status. OS was found to be significantly worse (p<0.01) only in women with stages II-IV tumors and those with residual disease after surgery (p<0.01). Overall, serous and endometrioid tumors were predominantly ER/PR positive, whereas mucinous and clear-cell tumors were preponderantly ER/PR negative. DFS and OS were not affected by ER/PR expression.

  6. Ltc1 is an ER-localized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts.

    Science.gov (United States)

    Murley, Andrew; Sarsam, Reta D; Toulmay, Alexandre; Yamada, Justin; Prinz, William A; Nunnari, Jodi

    2015-05-25

    Organelle contact sites perform fundamental functions in cells, including lipid and ion homeostasis, membrane dynamics, and signaling. Using a forward proteomics approach in yeast, we identified new ER-mitochondria and ER-vacuole contacts specified by an uncharacterized protein, Ylr072w. Ylr072w is a conserved protein with GRAM and VASt domains that selectively transports sterols and is thus termed Ltc1, for Lipid transfer at contact site 1. Ltc1 localized to ER-mitochondria and ER-vacuole contacts via the mitochondrial import receptors Tom70/71 and the vacuolar protein Vac8, respectively. At mitochondria, Ltc1 was required for cell viability in the absence of Mdm34, a subunit of the ER-mitochondria encounter structure. At vacuoles, Ltc1 was required for sterol-enriched membrane domain formation in response to stress. Increasing the proportion of Ltc1 at vacuoles was sufficient to induce sterol-enriched vacuolar domains without stress. Thus, our data support a model in which Ltc1 is a sterol-dependent regulator of organelle and cellular homeostasis via its dual localization to ER-mitochondria and ER-vacuole contact sites. © 2015 Murley et al.

  7. Identification of epidermal growth factor receptor-positive glioblastoma using lipid-encapsulated targeted superparamagnetic iron oxide nanoparticles in vitro

    Directory of Open Access Journals (Sweden)

    Huai-Lu Chen

    2017-11-01

    Full Text Available Abstract Background Targeted superparamagnetic iron oxide (SPIO nanoparticles have emerged as a promising biomarker detection tool for molecular magnetic resonance (MR image diagnosis. To identify patients who could benefit from Epidermal growth factor receptor (EGFR-targeted therapies, we introduce lipid-encapsulated SPIO nanoparticles and hypothesized that anti-EGFR antibody cetuximab conjugated of such nanoparticles can be used to identify EGFR-positive glioblastomas in non-invasive T2 MR image assays. The newly introduced lipid-coated SPIOs, which imitate biological cell surface and thus inherited innate nonfouling property, were utilized to reduce nonspecific binding to off-targeted cells and prevent agglomeration that commonly occurs in nanoparticles. Results The synthesized targeted EGFR-antibody-conjugated SPIO (EGFR-SPIO nanoparticles were characterized using dynamic light scattering, zeta potential assays, gel electrophoresis mobility shift assays, transmission electron microscopy (TEM images, and cell line affinity assays, and the results showed that the conjugation was successful. The targeting efficiency of the synthesized EGFR-SPIO nanoparticles was confirmed through Prussian blue staining and TEM images by using glioblastoma cell lines with high or low EGFR expression levels. The EGFR-SPIO nanoparticles preferentially targeted U-251 cells, which have high EGFR expression, and were internalized by cells in a prolonged incubation condition. Moreover, the T2 MR relaxation time of EGFR-SPIO nanoparticles could be used for successfully identifying glioblastoma cells with elevated EGFR expression in vitro and distinguishing U-251 cells from U-87MG cells, which have low EFGR expression. Conclusion These findings reveal that the lipid-encapsulated EGFR-SPIO nanoparticles can specifically target cells with elevated EGFR expression in the three tested human glioblastoma cell lines. The results of this study can be used for noninvasive

  8. Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC Uncovers Potential Novel Drivers of Hormonal Resistance.

    Directory of Open Access Journals (Sweden)

    Luis Manso

    Full Text Available We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC. We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11 of tumors (primary and metastases at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001. Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001, and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.

  9. Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.

    Science.gov (United States)

    Byun, Nellie E; Grannan, Michael; Bubser, Michael; Barry, Robert L; Thompson, Analisa; Rosanelli, John; Gowrishankar, Raajaram; Kelm, Nathaniel D; Damon, Stephen; Bridges, Thomas M; Melancon, Bruce J; Tarr, James C; Brogan, John T; Avison, Malcolm J; Deutch, Ariel Y; Wess, Jürgen; Wood, Michael R; Lindsley, Craig W; Gore, John C; Conn, P Jeffrey; Jones, Carrie K

    2014-06-01

    Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis

  10. Determination of estrogen receptor {beta}-mediated estrogenic potencies of hydroxylated PCBS by a yeast two-hybrid assay

    Energy Technology Data Exchange (ETDEWEB)

    Kuroki, H.; Kumate, M.; Nakaoka, H.; Yonekura, S. [Daiichi Coll. of Pharmaceutical Sciences, Fukuoka (Japan); Nishikawa, J.; Nishihara, T. [Osaka Univ., Osaka (Japan)

    2004-09-15

    Several environmental phenolic chemicals such as Nonylphenol and Bisphenol A (BPA) have been previously shown to possess estrogenic properties. In the previous paper, we have investigated the estrogenic activity of a series of hydroxylated PCBs (OH-PCBs) by a yeast two-hybrid assay (estrogen receptor{alpha} (ER{alpha}) -TIF2), in which the expression of estrogenic activity is based on the interaction of chemicals with ER{alpha}, and demonstrated that 4'-OH-CB30 and 4'-OH-CB61 are more estrogenic than BPA, one of the environmental estrogens. We have showed that one chlorine substitution adjacent to 4-OH at 3- or 5-position significantly reduces the ER{alpha}-mediated estrogenic activity of 4-OH-PCBs. Thus, 4'-OH-CB25 and 4-OH-CB56 showed a very weak estrogenicity. We have also showed that 4-OH-PCBs with two chlorine substitutions adjacent to 4-OH at 3- and 5-position such as 4'-OH-CB79 (hydroxylated metabolite of CB77) and persistent 4-OH-PCBs retained in human blood (4-OH-CB107, 4-OH-CB146 and 4-OH-CB187) have no ER{alpha}-mediated estrogenic activity. ER is known to have two subtypes, namely ER{alpha} and ER{beta} and it is reported that ligand, some agonist and antagonist have a different binding affinity for ER{alpha} and ER{beta}. However, there is limited information on ER{beta}-mediated endocrine disrupting potency. In this study, we examined the ER{beta}-mediated estrogenic activity of a series of OH-PCBs, including environmentally relevant 4-OH-PCBs by a yeast two-hybrid assay (ER{beta}-TIF2).

  11. 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

  12. Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABAA receptors and a homo-oligomeric GABA receptor from Drosophila melanogaster

    Science.gov (United States)

    Priestley, Caroline M; Williamson, Elizabeth M; Wafford, Keith A; Sattelle, David B

    2003-01-01

    The GABA-modulating and GABA-mimetic activities of the monoterpenoid thymol were explored on human GABAA and Drosophila melanogaster homomeric RDLac GABA receptors expressed in Xenopus laevis oocytes, voltage-clamped at −60 mV. The site of action of thymol was also investigated. Thymol, 1–100 μM, resulted in a dose-dependent potentiation of the EC20 GABA response in oocytes injected with either α1β3γ2s GABAA subunit cDNAs or the RDLac subunit RNA. At 100 μM thymol, current amplitudes in response to GABA were 416±72 and 715±85% of controls, respectively. On both receptors, thymol, 100 μM, elicited small currents in the absence of GABA. The EC50 for GABA at α1β3γ2s GABAA receptors was reduced by 50 μM thymol from 15±3 to 4±1 μM, and the Hill slope changed from 1.35±0.14 to 1.04±0.16; there was little effect on the maximum GABA response. Thymol (1–100 μM) potentiation of responses to EC20 GABA for α1β1γ2s, α6β3γ2s and α1β3γ2s human GABAA receptors was almost identical, arguing against actions at benzodiazepine or loreclezole sites. Neither flumazenil, 3-hydroxymethyl-β-carboline (3-HMC), nor 5α-pregnane-3α, 20α-diol (5α-pregnanediol) affected thymol potentiation of the GABA response at α1β3γ2s receptors, providing evidence against actions at the benzodiazepine/β-carboline or steroid sites. Thymol stimulated the agonist actions of pentobarbital and propofol on α1β3γ2s receptors, consistent with a mode of action distinct from that of either compound. These data suggest that thymol potentiates GABAA receptors through a previously unidentified binding site. PMID:14623762

  13. Mammographic features of calcifications in DCIS: correlation with oestrogen receptor and human epidermal growth factor receptor 2 status

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Min Sun; Moon, Woo Kyung; Chang, Jung Min; Cho, Nariya [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Park, So Yeon; Won, Jae-Kyung; Jeon, Yoon-Kyung; Park, In Ae [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Moon, Hyeong-Gon; Han, Wonshik [Seoul National University College of Medicine, Department of Surgery, Seoul (Korea, Republic of)

    2013-08-15

    This study investigated the correlation of oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status with the probability of malignancy (POM) of mammographic calcifications in ductal carcinoma in situ (DCIS). A total of 101 women (age range, 27-83 years) with pure DCIS that presented as mammographic calcifications were included. Three radiologists independently reviewed mammograms according to the BI-RADS lexicon and provided 100-point POM scores and a BI-RADS category. ER, HER2 and breast cancer subtypes were determined using immunohistochemistry (IHC) and fluorescence in situ hybridisation. Pairwise correlations between POM and IHC biomarker scores were calculated, and mammographic features were compared between breast cancer subtypes. HER2 level positively correlated with the POM score (P < 0.0001) and BI-RADS category (P < 0.0001), and ER level inversely correlated with the POM score (P < 0.013) and BI-RADS category (P < 0.010). Fine linear branching (P = 0.004) and segmental (P = 0.014) calcifications were significantly associated with HER2-positive cancers, and clustered calcifications were more frequently observed in ER-positive cancers (P = 0.014). HER2 status in DCIS correlated positively with the POM of mammographic calcifications, as determined by radiologists on the basis of the BI-RADS lexicon. (orig.)

  14. Er HR ude i tovene?

    DEFF Research Database (Denmark)

    Poulfelt, Flemming

    2015-01-01

    HR: Er der behov for nytænkning i HR-land? Artikler i Harvard Business Review - bakket op af en dansk undersøgelse - konkluderer, at HR stadig mangler gennemslagskraft i virksomhederne. Er HR ude i tovene? ... For i undersøgelsen "Ny Dansk Ledelse" (maj 2015), som er baseret på danske lederes...

  15. Hormonal Receptor, Human Epidermal Growth Factor and Its Association with Breast Cancer Tumor Characteristics in Albania.

    Science.gov (United States)

    Pajenga, Edlira; Rexha, Tefta; Çeliku, Silva; Ugrinska, Ana; Bejtja, Gazmend

    2016-09-01

    This retrospective study was designed to analyze expression patterns of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu in Albanian patients with breast carcinoma to identify their relationships with tumor size, histological grade (HG), lymph node metastasis and relapse. Patients with either biopsy or metastatic relapse were identified. Demographics, tumor characteristics, ER, PR, and HER2/neu status were retrospectively obtained from the medical records of patients treated with breast cancer during 2006-2011. Hormonal receptors and HER2/neu were assessed by immunohistochemistry. Association of ER, PR and HER2/neu with clinicopathological and molecular characteristics were studied using Fisher's test. P value ≤0.05 was considered significant. There were 110 patients included in the study. Mean patient age was 51.08±10.75 years. The overall immunoexpression of ER, PR and HER2/neu were found positive in 76 (69%), 73 (67%), and 16 (41%) patients, respectively. ER- was associated with higher histological grade (24% vs. 9.2%) and PR+ with tumor size (T2, 78.3 vs. 64.3) (p=0.02 and 0.05, respectively). ER and PR expression were significantly decreased in HER2/neu positive cases while HER2/neu levels correlated with tumor size (p=0.03) and nodal metastasis (p=0.03). No association was detected between ER, PR, HER2/neu and relapse. A combination of ER, PR and HER2/neu and prognostic factors could be of clinical value by defining subgroups in Albanian breast cancer patients that might benefit from more aggressive treatment.

  16. Facebook er internettet nu

    DEFF Research Database (Denmark)

    Tække, Jesper

    2014-01-01

    Den store vision for world wide web var, at alle kunne få ubegrænset adgang til alverdens information. www var mangfoldigt og anarkistisk. I dag er der rigtig mange, der kun bruger nettet til at være på Facebook. Hvad bruger Facebook det til? Og hvad gør det ved vores udsyn?......Den store vision for world wide web var, at alle kunne få ubegrænset adgang til alverdens information. www var mangfoldigt og anarkistisk. I dag er der rigtig mange, der kun bruger nettet til at være på Facebook. Hvad bruger Facebook det til? Og hvad gør det ved vores udsyn?...

  17. Hvad er en by?

    DEFF Research Database (Denmark)

    Parby, Jakob; Thelle, Mikkel

    2011-01-01

    Nytænkning. Med de moderne megabyer er det slut med at forestille sig byen som noget, man planlægger og giver form. Vi skal lære at se dem som vildtvoksende urbane landskaber. Artikel om megabyer, byudvikling og forestillingen om byen gennem tiderne. Skrevet delvist i anledning af åbningen af...... udstillingen Citambulos på Københavns Museum, der handlede om Mexico City....

  18. Hvis er Himmeriget?

    DEFF Research Database (Denmark)

    Holst, Søren

    2007-01-01

    Udtrykket "de fattige i ånden", som kendes fra Bjergprædikenen i Matthæusevangeliet, forekommer også i to af Dødehavsrullerne. Artiklen undersøger disse tekster og argumenterer for, at udtrykket ikke betegner en særligt "åndelig" fattigdom, men derimod de konkret økonomisk fattige, som er "af ånd...

  19. er 2000

    DEFF Research Database (Denmark)

    Jensen, J. P.; Søndergaard, M.; Jeppesen, E.

    ændringer i be-lastningen af vand-miljøet med nærings-salte. Med NOVA er programmet udvidet til at omfatte både vand-miljøets tilstand i bredeste forstand og miljøfremmede stoffer og tungmetaller. Danmarks Miljøundersø-gelser har som sektor-forskningsinstitu-tion i Miljøministeriet til opgave at forbedre og...

  20. Han er her endnu

    DEFF Research Database (Denmark)

    Bonde, Lisbeth

    2012-01-01

    Interview med den kinesiske aktivist og billedkunstner Ai Weiwei, der sad fængslet i 81 dage i 2011. Hans pas er stadig (i februar 2014) inddraget af myndighederne, så han kan ikke forlade landet, selv om han har betalt en bøde på 13 mio. kr. for ”skatteunddragelse”. Både i sin kunst og i sine ma...

  1. Evidence for an association of dietary flavonoid intake with breast cancer risk by estrogen receptor status is limited.

    Science.gov (United States)

    Wang, Ying; Gapstur, Susan M; Gaudet, Mia M; Peterson, Julia J; Dwyer, Johanna T; McCullough, Marjorie L

    2014-10-01

    Results from preclinical studies suggest that flavonoids, which are ubiquitous in plant-based diets, lower breast cancer risk. Epidemiologic studies of flavonoid intake and breast cancer risk, however, are limited, and few investigated associations with the more aggressive estrogen receptor (ER)-negative (ER-) tumors. We examined the associations between 7 subclasses of dietary flavonoids and invasive postmenopausal breast cancer risk overall and by ER status in a U.S. prospective cohort. In 1999-2000, 56,630 postmenopausal women completed detailed self-administered questionnaires, among whom 2116 invasive breast cancers were verified during a mean follow-up period of 8.5 y. Cox proportional hazards regression was used to calculate multivariable-adjusted HRs and 95% CIs. Total flavonoid intake was not associated with breast cancer risk. However, there was a modest inverse association between flavone intake and overall breast cancer risk (fifth vs. first quintile HR: 0.88; 95% CI: 0.76, 1.01; P-trend = 0.04) and between flavan-3-ol intake and risk of ER- breast cancer (for an increment of 40 mg/d; HR: 0.81; 95% CI: 0.67, 0.97) but not for ER-positive (ER+) breast cancer risk. The inverse association of flavan-3-ol intake with ER- but not ER+ breast cancer is consistent with other studies that suggest a beneficial role of plant-based diets in ER- breast cancer risk. © 2014 American Society for Nutrition.

  2. Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: A cohort study

    NARCIS (Netherlands)

    Ritte, R.; Lukanova, A.; Tjonneland, A.; Olsen, A.; Overvad, K.; Mesrine, S.; Fagherazzi, G.; Dossus, L.; Teucher, B.; Duijnhoven, van F.J.B.

    2013-01-01

    Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European

  3. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group

    DEFF Research Database (Denmark)

    Kyndi, M.; Sorensen, F.B.; Overgaard, M.

    2008-01-01

    -2+, Rec-/HER-2- (triple negative), and Rec-/HER-2+. Results A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall......Purpose To examine the importance of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and constructed subtypes in a large study randomly assigning patients to receive or not receive postmastectomy radiotherapy (PMRT). Patients and Methods...... The present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years...

  4. HPLC-Based Activity Profiling: Discovery of Piperine as a Positive GABAA Receptor Modulator Targeting a Benzodiazepine-Independent Binding Site

    Science.gov (United States)

    Zaugg, Janine; Baburin, Igor; Strommer, Barbara; Kim, Hyun-Jung; Hering, Steffen; Hamburger, Matthias

    2011-01-01

    A plant extract library was screened for GABAA receptor activity making use of a two-microelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 μg/mL] potentiated GABA-induced chloride currents through GABAA receptors (composed of α1, β2, and γ2S subunits) by 169.1 ± 2.4%. With the aid of an HPLC-based activity profiling approach, piperine (5) was identified as the main active compound, together with 12 structurally related less active or inactive piperamides (1–4, 6–13). Identification was achieved by on-line high-resolution mass spectrometry and off-line microprobe 1D and 2D NMR spectroscopy, using only milligram amounts of extract. Compound 5 induced a maximum potentiation of the chloride currents by 301.9 ± 26.5% with an EC50 of 52.4 ± 9.4 μM. A comparison of the modulatory activity of 5 and other naturally occurring piperamides enabled insights into structural features critical for GABAA receptor modulation. The stimulation of chloride currents through GABAA receptors by compound 5 was not antagonized by flumazenil (10 μM). These data show that piperine (5) represents a new scaffold of positive allosteric GABAA receptor modulators targeting a benzodiazepine-independent binding site. PMID:20085307

  5. Progesterone receptor levels independently predict survival in endometrial adenocarcinoma

    DEFF Research Database (Denmark)

    Nyholm, H C; Christensen, Ib Jarle; Nielsen, Anette Lynge

    1995-01-01

    Estrogen receptor (ER) and progesterone receptor (PR) contents were determined by biochemical (dextran charcoal-coated (DCC) assay) and immunohistochemical (ICA) methods in biopsies from 145 primary endometrial adenocarcinomas and those with eligible receptor measurements were analyzed with respect...

  6. Naltrexone ER/Bupropion ER: A Review in Obesity Management.

    Science.gov (United States)

    Greig, Sarah L; Keating, Gillian M

    2015-07-01

    Oral naltrexone extended-release/bupropion extended-release (naltrexone ER/bupropion ER; Contrave(®), Mysimba(™)) is available as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial body mass index (BMI) of ≥ 30 kg/m(2) (i.e. obese) or a BMI of ≥ 27 kg/m(2) (i.e. overweight) in the presence of at least one bodyweight-related comorbidity, such as type 2 diabetes mellitus, hypertension or dyslipidaemia. In 56-week phase III trials in these patient populations, oral naltrexone ER/bupropion ER 32/360 mg/day was significantly more effective than placebo with regard to percentage bodyweight reductions from baseline and the proportion of patients who achieved bodyweight reductions of ≥ 5 and ≥ 10%. Significantly greater improvements in several cardiometabolic risk factors were also observed with naltrexone ER/bupropion ER versus placebo, as well as greater improvements in glycated haemoglobin levels in obese or overweight adults with type 2 diabetes. Naltrexone ER/bupropion ER was generally well tolerated in phase III trials, with nausea being the most common adverse event. Thus, naltrexone ER/bupropion ER 32/360 mg/day as an adjunct to a reduced-calorie diet and increased physical activity, is an effective and well tolerated option for chronic bodyweight management in obese adults or overweight adults with at least one bodyweight-related comorbidity.

  7. The expression of receptors for estrogen and epithelial growth factor in the male rabbit prostate and prostatic urethra following castration

    DEFF Research Database (Denmark)

    Bødker, A; Balslev, E; Iversen, H G

    1997-01-01

    were included as controls. In the control group, ERs were found in the urothelial lining and lamina propria of the prostatic urethra, and in the prostatic stroma. EGF receptors were demonstrated in the epithelial lining of the prostatic urethra and the glandular epithelium of the prostate. Following...... castration, the expression of ERs, assessed as the increase in the number of positively stained specimens, increased significantly in the lamina propria of the prostatic urethra and the prostatic stroma. EGF receptor expression increased significantly in the epithelial lining of the prostatic urethra...

  8. 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

  9. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study

    DEFF Research Database (Denmark)

    Andersson, Michael; Lidbrink, Elisabeth; Bjerre, Karsten

    2011-01-01

    To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer.......To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer....

  10. Positive allosteric modulation of GABA-A receptors reduces capsaicin-induced primary and secondary hypersensitivity in rats

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Erichsen, Helle K; Brown, David T

    2012-01-01

    this concept being tested in humans. Prior to assessing the efficacy of GABA-A receptor PAMs in a human volunteer pain model we have compared compounds capable of variously modulating GABA-A receptor function in comparable rat models of capsaicin-induced acute nocifensive flinching behaviour and secondary...... mechanical hypersensitivity. The subtype-selective PAM NS11394 (0.3-10 mg/kg), and the non-selective PAM diazepam (1-5 mg/kg) variously reduced capsaicin-induced secondary mechanical hypersensitivity (180 min post-injection). However, the low efficacy subtype-selective PAM TPA023 (3-30 mg/kg) was completely......, albeit at doses previously shown to impair locomotor function. Our data indicate that GABA-A receptor PAMs with optimal selectivity and efficacy profiles reduce centrally-mediated mechanical hypersensitivity in capsaicin-injected rats, an observation that we expect can translate directly to human...

  11. CCN5/WISP-2 restores ER-∝ in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

    Science.gov (United States)

    Sarkar, S; Ghosh, A; Banerjee, S; Maity, G; Das, A; Larson, M A; Gupta, V; Haque, I; Tawfik, O; Banerjee, S K

    2017-05-22

    CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-α (ER-α) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-α. A unique molecular relation between CCN5 and ER-α has been established as the components of the same signaling pathway that coordinate some essential signals associated with the proliferation as well as delaying the disease progression from a non-invasive to invasive phenotypes. Given the importance of this connection, we determined the role of CCN5 in regulation of ER-α in different cellular settings and their functional relationship. In a genetically engineered mouse model, induced expression of CCN5 in the mammary ductal epithelial cells by doxycycline promotes ER-α expression. Similarly, CCN5 regulates ER-α expression and activity in normal and neoplastic breast cells, as documented in various in vitro settings such as mouse mammary gland culture, human mammary epithelial cell and different BC cell cultures in the presence or absence of human recombinant CCN5 (hrCCN5) protein. Mechanistically, at least in the BC cells, CCN5 is sufficient to induce ER-α expression at the transcription level via interacting with integrins-α6β1 and suppressing Akt followed by activation of FOXO3a. Moreover, in vitro and in vivo functional assays indicate that CCN5 treatment promotes response to tamoxifen in triple-negative BC (TNBC) cells possibly via restoring ER-α. Collectively, these studies implicates that the combination treatments of CCN5 (via activation of CCN5 or hrCCN5 treatment) and tamoxifen as potential therapies for TNBC.

  12. Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

    OpenAIRE

    Mauriac, L.; Keshaviah, A; Debled, M; Mouridsen, H; Forbes, Jf; Thürlimann, B; Paridaens, R; Monnier, A.; Láng, I.; Wardley, A; Nogaret, J-M; Gelber, RD; Castiglione-Gertsch, M.; Price, KN; Coates, AS

    2017-01-01

    Background: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. Patients and methods: Analyses included all 7707 eligible patient...

  13. Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Il Yong Chung

    Full Text Available The aim of this study was to determine the relationship between the body mass index (BMI at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS and breast-cancer-specific survival (BCSS outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS (P = 0.029, and BCSS (P = 0.013 in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS (adjusted hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 0.92 to 2.48 and significantly poorer BCSS (HR = 1.80, 95% CI = 1.08 to 2.99. In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS (HR = 0.44, 95% CI = 0.16 to 1.19 and BCSS (HR = 0.53, 95% CI = 0.19 to 1.44. Being underweight (BMI < 18.50 kg/m2 with hormone-receptor-negative breast cancer was associated with a significantly worse OS (HR = 1.98, 95% CI = 1.00-3.95 and BCSS (HR = 2.24, 95% CI = 1.12-4.47. There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer.

  14. Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration.

    Science.gov (United States)

    Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B; van der Hoorn, Frans A

    2016-07-15

    The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. How to target estrogen receptor-negative breast cancer?

    Science.gov (United States)

    Rochefort, H; Glondu, M; Sahla, M E; Platet, N; Garcia, M

    2003-06-01

    Estrogen receptor (ER)-positive breast cancers generally have a better prognosis and are often responsive to anti-estrogen therapy, which is the first example of a successful therapy targeted on a specific protein, the ER. Unfortunately ER-negative breast cancers are more aggressive and unresponsive to anti-estrogens. Other targeted therapies are thus urgently needed, based on breast cancer oncogene inhibition or suppressor gene activation as far as molecular studies have demonstrated the alteration of expression, or structure of these genes in human breast cancer. Using the MDA-MB.231 human breast cancer cell line as a model of ER-negative breast cancers, we are investigating two of these approaches in our laboratory. Our first approach was to transfect the ER or various ER-deleted variants into an ER-negative cell line in an attempt to recover anti-estrogen responsiveness. The unliganded receptor, and surprisingly estradiol, were both found to inhibit tumor growth and invasiveness in vitro and in vivo. The mechanisms of these inhibitions in ER-negative cancer cells are being studied, in an attempt to target the ER sequence responsible for such inhibition in these cancer cells. Another strategy is trying to inhibit the activity or expression of an oncogene specifically overexpressed in most breast cancers. This approach was recently shown by others to be efficient in breast cancer therapy with HER2-Neu oncogene amplification using Herceptin. Without excluding other molecular putative targets, we have focused our research on cathepsin D as a potential target, since it is often overexpressed in aggressive human breast cancers, including ER-negative tumors, and rarely associated with HER2-Neu amplification. Our first results obtained in vitro on cell lines and in vivo in tumor xenografts in nude mice, illustrate that the mode of action of cathepsin D in breast cancer is useful to guide the development of these therapies. In the past 20 years we have learned that the

  16. Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women.

    Science.gov (United States)

    Proctor, Erica; Kidwell, Kelley M; Jiagge, Evelyn; Bensenhaver, Jessica; Awuah, Baffour; Gyan, Kofi; Toy, Kathy; Oppong, Joseph Kwaku; Kyei, Ishmael; Aitpillah, Francis; Osei-Bonsu, Ernest; Adjei, Ernest; Ohene-Yeboah, Michael; Brewer, Robert Newman; Fondjo, Linda Ahenkorah; Owusu-Afriyie, Osei; Wicha, Max; Merajver, Sofia; Kleer, Celina; Newman, Lisa

    2015-11-01

    The androgen receptor (AR) is a commonly-expressed hormone receptor in breast cancer and may be a marker of response to targeted anti-androgen therapy, a particularly attractive option for triple-negative breast cancer (TNBC). Gene expression studies suggest that ARs may distinguish a luminal/AR TNBC subtype from stem cell-like subtypes. TNBC frequency is two to three times higher in African American and African breast cancers compared with White American and European breast cancers, yet little is known regarding TNBC subtypes in high-frequency African-ancestry populations. We evaluated ARs and the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) among breast cancers from Ghana, Africa. Overall, 147 formalin-fixed, paraffin-embedded invasive breast cancers from the Komfo Anoyke Teaching Hospital in Ghana were studied at the University of Michigan, and analyzed immunohistochemically for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, ALDH1, and AR expression. The median age of patients was 45 years. Only 31 cases (21 %) were ER-positive, and 14 (10 %) were HER2-positive; 89 (61 %) were TNBCs. For the entire group, 44 % were AR-positive and 45 % were ALDH1-positive. ER/PR-positive tumors were more likely to be AR-positive compared with ER/PR-negative tumors (87 vs. 26 %; p Africa. Surprisingly, ALDH1 was found to correlate with AR expression among TNBC, suggesting that novel TNBC subtypes may exist among populations with African ancestry.

  17. Conversion of hormone and HER-2 receptor in metachronous neck metastases from breast carcinoma.

    Science.gov (United States)

    Nauroth, Andreas; Kalder, Matthias; Rössler, Marion; Wichmann, Gunnar; Dietz, Andreas; Wiegand, Susanne

    2017-04-20

    Metastases are a common event in breast cancer. The expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) is essential for therapy and prognosis, and their conversion during disease progression potentially affects the treatment regimen. The aim was to analyze the estrogen, progesterone and HER-2 receptor expression in primary tumors and metachronous neck metastases from patients with breast cancer. A retrospective analysis of 27 patients with breast cancer and metachronous neck metastasis was performed. Distribution of neck metastasis to the neck levels and estrogen, progesterone and HER-2 receptor expression in primary tumor and metastasis were examined. The most common localization of neck metastasis was level V. ER, PR, and HER-2 in primary tumors were positive in 48.1, 51.9, and 26.3% of patients, respectively. A loss of ER and PR in neck metastasis was observed in 22.2 and 40.7% of the patients, respectively. HER-2 change was present in 4 of 19 paired samples (21.0%). The expression of ER, PR and HER-2 in neck metastases can be expected to diverge from the expression of these markers in the primary tumor. As such changes can occur during disease progression, the evaluation of biomarkers in metastatic sites should be mandatory, whenever possible, to ensure that patients are receiving the most effective treatment at all times.

  18. Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

    NARCIS (Netherlands)

    C. Poyet (Cédric); T. Hermanns (Thomas); Q. Zhong (Qing); E. Drescher (Eva); D. Eberli (Daniel); M. Burger (Maximilian); F. Hofstaedter (Ferdinand); A. Hartmann (Arndt); R. Stöhr (Robert); E.C. Zwarthoff (Ellen); T. Sulser (Tullio); P.J. Wild (Peter J.)

    2015-01-01

    textabstractIn addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical

  19. Family history and breast cancer hormone receptor status in a Spanish cohort.

    Directory of Open Access Journals (Sweden)

    Xuejuan Jiang

    Full Text Available BACKGROUND: Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. MATERIALS AND METHODS: A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. RESULTS: Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+ or progesterone receptor-positive (PR+, and 22% were ER-&PR-. Women with a family history of breast cancer were more likely to have ER-&PR- tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91-2.26. This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34-5.81. CONCLUSIONS: An increased proportion of ER-&PR- breast cancer was observed among younger Spanish women with a family history of the disease.

  20. Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

    Directory of Open Access Journals (Sweden)

    Douglas Bledsoe

    2017-05-01

    Full Text Available N-methyl D-aspartate receptors (NMDAR play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D and two GluN3 (A–B subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD and ligand binding domain (LBD, transmembrane domain (TMD and an intracellular C-terminal domain (CTD. Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

  1. Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, Joan S. [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States); Jordan, V. Craig [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States)]. E-mail: v.craig.jordan@fccc.edu

    2005-12-11

    Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17{beta}-estradiol (E{sub 2}), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER{alpha} or ER{beta}, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

  2. A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.

    Science.gov (United States)

    Chia, Stephen K; Ellard, Susan L; Mates, Mihaela; Welch, Stephen; Mihalcioiu, Catalin; Miller, Wilson H; Gelmon, Karen; Lohrisch, Caroline; Kumar, Vikaash; Taylor, Sara; Hagerman, Linda; Goodwin, Rachel; Wang, Tao; Sakashita, Shingo; Tsao, Ming S; Eisenhauer, Elizabeth; Bradbury, Penelope

    2017-05-02

    The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC). Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed. We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34-86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1-20) with associated progression-free survival of 3.2 months (95% CI 1.61-4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met. The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this

  3. The anti-metastatic effects of the phytoestrogen arctigenin on human breast cancer cell lines regardless of the status of ER expression.

    Science.gov (United States)

    Maxwell, Thressi; Chun, So-Young; Lee, Kyu-Shik; Kim, Soyoung; Nam, Kyung-Soo

    2017-02-01

    Arctigenin is a plant lignan extracted from Arctium lappa that has been shown to have estrogenic properties. In spite of the health benefits of phytoestrogens reducing the risk of osteoporosis, heart disease, and menopausal symptoms, its benefits against the risk of breast cancer have not been fully elucidated. Thus, we investigated the effects of arctigenin on metastasis of breast cancer using both estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cell lines to see if the effects are dependent on the status of ER expression. In ER-positive MCF-7 cells, arctigenin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and invasion. The activity of crucial metastatic protease matrix metalloprotease (MMP)-9 in gelatin zymography was also efficiently decreased by arctigenin, as well as its mRNA expression. Notably, arctigenin exhibited similar anti-metastatic effects even in ER-negative MDA-MB-231 cells, suggesting that the anti-metastatic effects of arctigenin were not exerted via the ER. The upstream signaling pathways involved in the regulation of MMP-9 and urokinase plasminogen activator (uPA) were analyzed using western blotting. The activation of Akt, NF-κB and MAPK (ERK 1/2 and JNK 1/2) was found to be inhibited. Taken together, these data suggest that arctigenin confers anti-metastatic effects by inhibiting MMP-9 and uPA via the Akt, NF-κB and MAPK signaling pathways on breast cancer, regardless of ER expression. Therefore, we propose that the intake of arctigenin could be an effective supplement for breast cancer patients.

  4. A REACTIVITY PATTERN OF DISCRIMINATION OF ER AGONISM AND ANTAGONISM BASED ON 3-D MOLECULAR ATTRIBUTES

    Science.gov (United States)

    Various models have been developed to predict the relative binding affinity (RBA) of chemicals to estrogen receptors (ER). These models are important for prioritizing chemicals for screening in biological assays assessing the potential for endocrine disruption. One shortcoming of...

  5. Similarities and differences in structure, expression, and functions of VLDLR and ApoER2

    Directory of Open Access Journals (Sweden)

    Weeber Edwin J

    2011-05-01

    Full Text Available Abstract Very Low Density Lipoprotein Receptor (VLDLR and Apolipoprotein E Receptor 2 (ApoER2 are important receptors in the brain for mediating the signaling effects of the extracellular matrix protein Reelin, affecting neuronal function in development and in the adult brain. VLDLR and ApoER2 are members of the low density lipoprotein family, which also mediates the effects of numerous other extracellular ligands, including apolipoprotein E. Although VLDLR and ApoER2 are highly homologous, they differ in a number of ways, including structural differences, expression patterns, alternative splicing, and binding of extracellular and intracellular proteins. This review aims to summarize important aspects of VLDLR and ApoER2 that may account for interesting recent findings that highlight the unique functions of each receptor.

  6. Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia

    Directory of Open Access Journals (Sweden)

    Yasunori Oda

    2015-12-01

    Full Text Available Although the dopamine D2 receptor (DRD2 has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%–30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s, is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.

  7. Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone.

    Science.gov (United States)

    Wang, Jianping; Lu, Zhengfang; Fu, Xiaojie; Zhang, Di; Yu, Lie; Li, Nan; Gao, Yufeng; Liu, Xianliang; Yin, Chunmao; Ke, Junji; Li, Liyuan; Zhai, Mengmeng; Wu, Shiwen; Fan, Jiahong; Lv, Liang; Liu, Junchao; Chen, Xuemei; Yang, Qingwu; Wang, Jian

    2017-05-27

    Choline acetyltransferase-positive (ChAT + ) neurons within the subventricular zone (SVZ) have been shown to promote neurogenesis after stroke in mice by secreting acetylcholine (ACh); however, the mechanisms remain unclear. Receptors known to bind ACh include the nicotinic ACh receptors (nAChRs), which are present in the SVZ and have been shown to be important for cell proliferation, differentiation, and survival. In this study, we investigated the neurogenic role of the alpha-7 nAChR (α7 nAChR) in a mouse model of middle cerebral artery occlusion (MCAO) by using α7 nAChR inhibitor methyllycaconitine. Mice subjected to MCAO exhibited elevated expression of cytomembrane and nuclear fibroblast growth factor receptor 1 (FGFR1), as well as increased expression of PI3K, pAkt, doublecortin (DCX), polysialylated - neuronal cell adhesion molecule (PSA-NCAM), and mammalian achaete-scute homolog 1 (Mash1). MCAO mice also had more glial fibrillary acidic protein (GFAP)/5-bromo-2'-deoxyuridine (BrdU)-positive cells and DCX-positive cells in the SVZ than did the sham-operated group. Methyllycaconitine treatment increased cytomembrane FGFR1 expression and GFAP/BrdU-positive cells, upregulated the levels of phosphoinositide 3-kinase (PI3K) and phospho-Akt (pAkt), decreased nuclear FGFR1 expression, decreased the number of DCX-positive cells, and reduced the levels of DCX, PSA-NCAM, and Mash1 in the SVZ of MCAO mice compared with levels in vehicle-treated MCAO mice. MCAO mice treated with α7 nAChR agonist PNU-282987 exhibited the opposite effects. Our data show that α7 nAChR may decrease the proliferation of neural stem cells and promote differentiation of existing neural stem cells after stroke. These results identify a new mechanism of SVZ ChAT + neuron-induced neurogenesis.

  8. Dynamics of GnRH Neuron Ionotropic GABA and Glutamate Synaptic Receptors Are Unchanged during Estrogen Positive and Negative Feedback in Female Mice.

    Science.gov (United States)

    Liu, Xinhuai; Porteous, Robert; Herbison, Allan E

    2017-01-01

    Inputs from GABAergic and glutamatergic neurons are suspected to play an important role in regulating the activity of the gonadotropin-releasing hormone (GnRH) neurons. The GnRH neurons exhibit marked plasticity to control the ovarian cycle with circulating estradiol concentrations having profound "feedback" effects on their activity. This includes "negative feedback" responsible for suppressing GnRH neuron activity and "positive feedback" that occurs at mid-cycle to activate the GnRH neurons to generate the preovulatory luteinizing hormone surge. In the present study, we employed brain slice electrophysiology to question whether synaptic ionotropic GABA and glutamate receptor signaling at the GnRH neuron changed at times of negative and positive feedback. We used a well characterized estradiol (E)-treated ovariectomized (OVX) mouse model to replicate negative and positive feedback. Miniature and spontaneous postsynaptic currents (mPSCs and sPSCs) attributable to GABA A and glutamatergic receptor signaling were recorded from GnRH neurons obtained from intact diestrous, OVX, OVX + E (negative feedback), and OVX + E+E (positive feedback) female mice. Approximately 90% of GnRH neurons exhibited spontaneous GABA A -mPSCs in all groups but no significant differences in the frequency or kinetics of mPSCs were found at the times of negative or positive feedback. Approximately 50% of GnRH neurons exhibited spontaneous glutamate mPSCs but again no differences were detected. The same was true for spontaneous PSCs in all cases. These observations indicate that the kinetics of ionotropic GABA and glutamate receptor synaptic transmission to GnRH neurons remain stable across the different estrogen feedback states.

  9. Novel positive regulatory role for the SPL6 transcription factor in the N TIR-NB-LRR receptor-mediated plant innate immunity.

    Directory of Open Access Journals (Sweden)

    Meenu S Padmanabhan

    2013-03-01

    Full Text Available Following the recognition of pathogen-encoded effectors, plant TIR-NB-LRR immune receptors induce defense signaling by a largely u