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Sample records for progesterone receptor positivity

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

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    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.

  2. 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

  3. 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

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

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    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.

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

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    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.

  6. 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.

  7. 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 ...

  8. 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.

  9. Estrogen and progesterone receptors in gynecomastia.

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    Pensler, J M; Silverman, B L; Sanghavi, J; Goolsby, C; Speck, G; Brizio-Molteni, L; Molteni, A

    2000-10-01

    The etiology of gynecomastia is unknown. There seems to be no increased incidence of malignancies in patients with idiopathic gynecomastia; however, patients with Klinefelter syndrome exhibit an increased incidence of malignancy. The authors reviewed the results of 34 patients with gynecomastia diagnosed in adolescence who, following initial evaluation, had a mastectomy. The estrogen and progesterone receptors were analyzed in these patients. Three of the patients were diagnosed with Klinefelter syndrome. These three patients exhibited elevated amounts of estrogen and progesterone receptors. None of the patients who were not diagnosed with this syndrome demonstrated significant elevation of their estrogen or progesterone receptors. The presence of elevated estrogen and progesterone receptors in patients with Klinefelter syndrome provides a potential mechanism by which these patients may develop breast neoplasms. The absence of elevated estrogen and progesterone receptors in patients with idiopathic gynecomastia may serve to clarify why these patients' disease rarely degenerates into malignancy.

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

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    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.

  11. Distribution of estrogen and progesterone receptors in Epulis Fissuratum

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    Shahrabi Sh.

    2005-06-01

    Full Text Available Statement of Problem: Epulides Fissurata (EF are common proliferative and denture- induced lesions of the oral cavity with a predilection for female. This suggests a possible role for sex steroid hormones in the development and progression of these lesions. Purpose: The objective of this study was the immunohistochemical evaluation of epulis fissuratum of the oral cavity for estrogen and progesterone receptors expression in epithelial, stromal, inflammatory and endothelial cells populations. Materials and Methods: In this cross-sectional study, 15 samples of formalin- fixed, paraffin- embedded epulis fissuratums including marginal mucosal tissues in 4 cases as a control group, were immuno-histochemically evaluated for estrogen and progesterone receptors protein expression. Result: In 10 cases, estrogen receptor positivity was found within the epithelium and progesterone receptor immunoreactivity was present in 7 cases. Stromal cells exhibited estrogen and progesterone receptor immunostaining in many cases but only few cases showed expression of these receptors in the inflammatory and endothelial cells. Estrogen and progesterone receptors were also detected in some cases containing salivary glands tissue. Conclusion: Although chronic irritation may be the initiating factor for the occurence of epulis fissuratum, some of the cells in the lesion, could be potential targets for estrogen and progestrone hormones.

  12. Progesterone Receptor Scaffolding Function in Breast Cancer

    Science.gov (United States)

    2012-10-01

    response. PR are expressed in multiple human tissues including the uterus, mammary gland , brain, pancreas, thymus , bone, ovary, testes, and in the...ABSTRACT Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin...receptors (PR) are critical for massive breast epithelial cell expansion during mammary gland development and contribute to breast cancer progression

  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. 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...

  16. 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)

    Science.gov (United States)

    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

  17. Immunohistochemical Expression of Estrogen and Progesterone Receptors in Epulis Fissuratum

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    Maryam Seyedmajidi

    2013-01-01

    Full Text Available Background: Epulis Fissuratum (Epulis Fissuratum (EF or Denture Epulis or inflammatory fibrous hyperplasia is a common hyperplastic tumor-like lesion with reactive nature, related to loose and ill-fitting, full or partial removable dentures and it is more common in women than men. For this reason, hormonal influences may also play role in its creation. The effect of steroid hormones especially sex hormones (Estrogen and progesterone on oral mucosa is identified in some studies. In the present study, the distribution pattern and presence of estrogen and progesterone receptors in epithelial, stromal, endothelial and inflammatory cells in Epulis Fissuratum was investigated. Materials and Methods: This cross-sectional study was carried out on 30 samples of paraffin blocks with Epulis Fissuratum diagnosis and 30 samples of normal mucosal tissues as a control group who have had surgery as a margin beside the above lesions and had been obtained from the oral and maxillofacial pathology departement of Babol Dental School since 2003 up to 2010. Intensity of staining and immunoreactivity were evaluated using subjective index and considering the positive control group (breast carcinoma.Results: Epithelial, stromal, endothelial and inflammatory cells didn’t show reaction with monoclonal antibodies against estrogen and progesterone in none of the samples. Conclusion: It seems that the hypothesis of the existence of estrogen and progesterone receptors in epulis fissuratum and normal oral mucosa is ruled out. The possibility of direct effect of estrogen and progesterone in occurring of epulis fissuratum is rejected.

  18. Estrogen and progesterone receptors in human breast cancer. Correlation with histologic subtype and degree of differentiation.

    Science.gov (United States)

    Mohammed, R H; Lakatua, D J; Haus, E; Yasmineh, W J

    1986-09-01

    Microscopic review of 490 consecutive human breast biopsy and mastectomy specimens were correlated with estrogen and progesterone receptor content of the tissue, by subtype and degree of differentiation. Of the 4 grades of differentiation, the less differentiated Grade III and IV tumors showed significantly lower levels of estrogen and progesterone receptors in infiltrating ductal and lobular carcinoma (P less than 0.001). In contrast, patients with medullary carcinoma had the lowest tissue levels of estrogen and progesterone receptors with approximately 80% of the cases with less than 10 fmol/mg protein. Patients with mucinous carcinoma had the highest percentages of positive estrogen and progesterone receptor levels (75% and 87%, respectively). Sixty-three percent of the patients with Grade IV infiltrating ductal carcinoma were younger than 53 years of age (P less than 0.001). Patients younger than 53 years of age with Grade II and III infiltrating ductal carcinoma also had significantly lower levels of estrogen receptors, but not of progesterone receptors, than those patients older than 53 years of age (P less than 0.001). Nineteen of 20 "normal" breast tissue specimens were negative (less than 3 fmol/mg protein) for estrogen and progesterone receptors. About 50% of 17 tissue specimens from benign breast lesions (fibroadenoma, fibrocystic disease, sclerosing adenosis) showed positive estrogen (greater than 10 fmol/mg protein) or progesterone receptor values. In two patients with gynecomastia, no estrogen or progesterone receptors were detectable.

  19. 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.

  20. 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...

  1. Progesterone receptor structure and protease activity in primary human endometrial carcinoma.

    Science.gov (United States)

    Feil, P D; Clarke, C L; Satyaswaroop, P G

    1988-03-01

    Monoclonal antibodies were used to investigate progesterone receptor structure (isoforms) in 33 primary human endometrial tumors. The monoclonal antibodies recognized on protein blots two progesterone receptor proteins with molecular weights of 116,000 and 81,000. The Mr 116,000 protein appeared as a triplet, while a single band was found for the Mr 81,000 protein. The triplet/singlet structure was found in all progesterone receptor-positive tumors, regardless of the degree of tumor differentiation. Protease activity, which gave rise to a false-negative pattern on protein blots, was found in approximately one-half of the tumors in which it was investigated. Inclusion of a cocktail of protease inhibitors during sample preparation resulted in the maintenance of the triplet/singlet progesterone receptor structure. Mixing experiments using a progesterone receptor-rich human endometrial carcinoma (EnCa 101), which lacks protease activity, and protease-containing primary tumor homogenates indicated that the protease was leupeptin sensitive. Interestingly, while the proteolytic activity reduced or eliminated the triplet/singlet progesterone receptor structure seen on protein blot analysis, it did not affect progesterone receptor concentration measured by Scatchard analysis. Sample preparation in the presence of protease inhibitors is therefore a requisite for structural analysis of the progesterone receptor in endometrial tumors.

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

    Science.gov (United States)

    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/.

  3. 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

  4. 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

  5. Progesterone receptor content in endometrial carcinoma correlates with serum levels of free estradiol

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

    1993-01-01

    cytosol by dextran charcoal-coated assay and immunohistochemically on frozen sections. Serum sex hormones were measured by radioimmunoassays. MAIN FINDINGS. Tumor biochemical progesterone receptor content correlated positively (p

  6. Progesterone, Estradiol and their Receptors in Leiomyomata and the

    African Journals Online (AJOL)

    Estradiol and progesterone binding in uterine leiomyomata and in normal uterine tissues. Obstetrics and. Gynaecology. 1980; 55: 4-20. 4. Jorge RP, Edgrad C, Jacques G,. Christine V, Bernard S and Albert N. Effect of Decapeptyl, an agonist analog of GnRH on estrogens, estrogen sulfates, and progesterone receptors in.

  7. Progesterone receptor content in endometrial carcinoma correlates with serum levels of free estradiol

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

    1993-01-01

    between estrogen receptor content and any of the serum sex hormones. The progesterone/estrogen receptor ratio, calculated from the biochemical values, correlated positively (p levels of free estradiol. This relation was not affected by tumor histologic grade or stage. Furthermore......OBJECTIVE. To study a possible relationship between serum levels of estrogens and androgens and the tumor content of estrogen receptors and progesterone receptors in endometrial cancer. STUDY DESIGN. Fifty postmenopausal patients were included. Receptors were determined biochemically in tissue...... cytosol by dextran charcoal-coated assay and immunohistochemically on frozen sections. Serum sex hormones were measured by radioimmunoassays. MAIN FINDINGS. Tumor biochemical progesterone receptor content correlated positively (p levels. No correlations were observed...

  8. Progesterone receptor expression declines in the guinea pig uterus during functional progesterone withdrawal and in response to prostaglandins.

    Directory of Open Access Journals (Sweden)

    Toni N Welsh

    Full Text Available Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone

  9. Progesterone Receptor Expression Declines in the Guinea Pig Uterus during Functional Progesterone Withdrawal and in Response to Prostaglandins

    Science.gov (United States)

    Welsh, Toni N.; Hirst, Jonathan J.; Palliser, Hannah; Zakar, Tamas

    2014-01-01

    Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote

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

    Directory of Open Access Journals (Sweden)

    Pandey Rakesh

    2009-11-01

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

  11. Immunohistochemical assessment of oestrogen and progesterone receptors

    DEFF Research Database (Denmark)

    Grabau, D A; Thorpe, S M; Knoop, A

    2000-01-01

    Two different methods to determine steroid receptors were analysed with respect to their ability to estimate prognosis in primary breast cancer patients. The immunohistochemical assay (IHA) was compared with the dextran-coated charcoal (DCC) method of receptor determination. A random sample of 281...... of patients, receptor positive cases fared better than negative cases in all situations. Investigation of the prognostic power revealed that classification based on IHA allowed better discrimination of patients than classification based on the DCC method. The reason for this difference might be because...

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

    Science.gov (United States)

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

    2017-09-11

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

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

    Science.gov (United States)

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

    2014-02-01

    A 21-gene recurrence score (RS) assay provides a method of guiding treatment decisions in women with early-stage breast cancer (ESBC). We investigated the cost effectiveness of using the RS assay versus current clinical practice (CCP) in post-menopausal women with estrogen- or progesterone-receptor-positive, one to three positive axillary lymph-node ESBC from the perspective of the Canadian public healthcare system. We developed a decision analytic model to project the lifetime clinical and economic consequences of ESBC. We assumed that the RS assay would classify patients among risk levels (low, intermediate and high) and corresponding adjuvant treatment regimens. The model was parameterized using 7-year follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. Costs are presented in 2012 Canadian dollars, and future costs and benefits were discounted at 5 %. In the base case analysis, the RS assay compared with CCP led to an increase of 0.08 quality-adjusted life-year (QALY) and an increase in cost of Can$36.2 per person, resulting in an incremental cost-effectiveness ratio (ICER) of Can$464/QALY gained. The ICER was most sensitive to the proportion of women classified to intermediate risk by the RS assay who received adjuvant chemotherapy, and absolute risk of relapse among patients receiving the RS assay. The RS assay is likely to be cost effective in the Canadian healthcare system. Field evaluations of the assay in this patient population will help reduce uncertainty in clinical guidelines for intermediate-range RS-assay values and specific disease outcomes by the RS assay, which are important drivers of ICER.

  14. Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer.

    Directory of Open Access Journals (Sweden)

    Tamar Kavlashvili

    Full Text Available Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR. However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term "molecularly enhanced progestin therapy." What remained unclear was the mechanism of action and if estrogen receptor α (ERα, the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data

  15. Progesterone

    Science.gov (United States)

    ... cancer. Progesterone is also used to bring on menstruation (period) in women of childbearing age who have ... in the uterus. It works to bring on menstruation by replacing the natural progesterone that some women ...

  16. Estrogen and Progesterone hormone receptor expression in oral cavity cancer.

    Science.gov (United States)

    Grimm, M; Biegner, T; Teriete, P; Hoefert, S; Krimmel, M; Munz, A; Reinert, S

    2016-09-01

    Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible. Estrogen Receptor alpha (ERα) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERα and PR expression. ERα expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERα positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERα and PR. ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC.

  17. 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.

  18. 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

  19. ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors

    OpenAIRE

    Hertz, Daniel L.; Henry, N. Lynn; Kidwell, Kelley M.; Thomas, Dafydd; Goddard, Audrey; Azzouz, Faouzi; Speth, Kelly; Li, Lang; Banerjee, Mousumi; Thibert, Jacklyn N; Kleer, Celina G.; Stearns, Vered; Hayes, Daniel F.; Skaar, Todd C.; Rae, James M.

    2016-01-01

    Hormone receptor-positive (HR+) breast cancers express the estrogen (ERα) and/or progesterone (PgR) receptors. Inherited single nucleotide polymorphisms (SNPs) in ESR1, the gene encoding ERα, have been reported to predict tamoxifen effectiveness. We hypothesized that these associations could be attributed to altered tumor gene/protein expression of ESR1/ERα and that SNPs in the PGR gene predict tumor PGR/PgR expression. Formalin-fixed paraffin-embedded breast cancer tumor specimens were analy...

  20. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  1. Novel Progesterone Receptors: Neural Localization and Possible Functions

    Directory of Open Access Journals (Sweden)

    Sandra L Petersen

    2013-09-01

    Full Text Available Progesterone (P4 regulates a wide range of neural functions and likely acts through multiple receptors. Over the past 30 years, most studies investigating neural effects of P4 focused on genomic and non-genomic actions of the classical progestin receptor (PGR. More recently the focus has widened to include two groups of non-classical P4 signaling molecules. Members of the Class II progestin and adipoQ receptor (PAQR family are called membrane progestin receptors (mPRs and include: mPRα (PAQR7, mPRβ (PAQR8, mPRγ (PAQR5, mPRδ (PAQR6 and mPRε (PAQR9. Members of the b5-like heme/steroid-binding protein family include progesterone receptor membrane component 1 (PGRMC1, PGRMC2, neudesin and neuferricin. Results of our recent mapping studies show that members of the PGRMC1/S2R family, but not mPRs, are quite abundant in forebrain structures important for neuroendocrine regulation and other non-genomic effects of P4. Herein we describe the structures, neuroanatomical localization and signaling mechanisms of these molecules. We also discuss possible roles for Pgrmc1/S2R in gonadotropin release, feminine sexual behaviors, fluid balance and neuroprotection, as well as catamenial epilepsy.

  2. Estrogen and progesterone receptors in human breast cancer. Correlation with histologic subtype and degree of differentiation

    National Research Council Canada - National Science Library

    Mohammed, R H; Lakatua, D J; Haus, E; Yasmineh, W J

    1986-01-01

    Microscopic review of 490 consecutive human breast biopsy and mastectomy specimens were correlated with estrogen and progesterone receptor content of the tissue, by subtype and degree of differentiation...

  3. Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer

    OpenAIRE

    Hanekamp, Eline; Blok, Leen; Gielen, Susanne; Smid-Koopman, Ellen; Kühne, Liesbeth; Ruiter, Petra; Chadha-Ajwani, Savi; Brinkmann, Albert; Grootegoed, Anton; Burger, Curt; Huikeshoven, Frans

    2003-01-01

    textabstractPURPOSE: In endometrial cancer, loss of progesterone receptors (PR) is associated with more advanced disease. This study aimed to investigate the mechanism of action of progesterone and the loss of its receptors (PRA and PRB) in development of endometrial cancer. EXPERIMENTAL DESIGN: A 9600-cDNA microarray analysis was performed to study regulation of gene expression in the human endometrial cancer subcell line Ishikawa PRAB-36 by the progestagen medroxy progesterone acetate (MPA)...

  4. Progesterone receptor modulates ERα action in breast cancer.

    Science.gov (United States)

    Mohammed, Hisham; Russell, I Alasdair; Stark, Rory; Rueda, Oscar M; Hickey, Theresa E; Tarulli, Gerard A; Serandour, Aurelien A; Serandour, Aurelien A A; Birrell, Stephen N; Bruna, Alejandra; Saadi, Amel; Menon, Suraj; Hadfield, James; Pugh, Michelle; Raj, Ganesh V; Brown, Gordon D; D'Santos, Clive; Robinson, Jessica L L; Silva, Grace; Launchbury, Rosalind; Perou, Charles M; Stingl, John; Caldas, Carlos; Tilley, Wayne D; Carroll, Jason S

    2015-07-16

    Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

  5. Progesterone Inhibits Human Myometrial Contractions by Action on Membrane Receptors

    Directory of Open Access Journals (Sweden)

    Remzi Gokdeniz

    2013-02-01

    Full Text Available Background: The mechanisms for myometrial inhibition are still being investigated Aim: To examine mechanisms of progesterone (P4 inhibition of uterine contractility. Methods: Prospective study Tertiary care center at St. Joseph’s Hospital and at Maricopa Hospital, Phoenix, AZ and research center in Arizona, USA. During 2010-2011, 24 women given birth by cesarean section. Uterine tissues from women (n=24 at term were suspended in organ chambers and exposed to various agents. Contractility was registered and compared before and after addition of agents. Tissues were treated with P4 alone, a progestin (R5020 with low affinity to the progesterone membrane receptor (mPR, or a non-sex steroid (cholesterol. Other tissues were pretreated with inhibitors of adenylate cyclase (SQ 22536, phosphodiesterase (rolipram, nitric oxide (NO synthases (L-NAME or a nuclear P4 receptor antagonist (mifepristone, MIF, followed by P4. Data were analyzed by ANOVA. Results: P4 (P0.05 inhibitory effects. P4 inhibition is not blocked by MIF, SQ, ODQ, rolipram or L-NAME (P>0.05. Conclusions: P4 rapidly inhibits myometrial contractility by nongenomic mechanisms through action on mPR but not via cAMP, cGMP, or NO [Cukurova Med J 2013; 38(1.000: 92-102

  6. Expression of Oestrogen and progesterone receptors, Ki-67,p53 and ...

    African Journals Online (AJOL)

    Expression of Oestrogen and progesterone receptors, Ki-67,p53 and bcl-2 proteins, cathepsin D, urokinase plasminogen activator and urokinase plasminogen activator-receptors in carcinomas of the female breast in an African population.

  7. Estrogen and progesterone receptors in endometrial carcinoma: comparison of immunohistochemical and biochemical analysis

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

    1993-01-01

    In 159 endometrial carcinomas, estrogen (ER) and progesterone receptors (PR) were determined biochemically by dextran-coated charcoal (DCC) assay and immunohistochemically (ICA) on frozen sections. ICA receptor content was estimated by a total histologic score (HSCORE), including all tissue...

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

    Directory of Open Access Journals (Sweden)

    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 ER-α positive (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 ER-α positive 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.

  9. 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

  10. Expression of estrogen and progesterone receptors in astrocytomas: a literature review

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    Cléciton Braga Tavares

    Full Text Available Gliomas are the most common type of primary central nervous system neoplasm. Astrocytomas are the most prevalent type of glioma and these tumors may be influenced by sex steroid hormones. A literature review for the presence of estrogen and progesterone receptors in astrocytomas was conducted in the PubMed database using the following MeSH terms: “estrogen receptor beta” OR “estrogen receptor alpha” OR “estrogen receptor antagonists” OR “progesterone receptors” OR “astrocytoma” OR “glioma” OR “glioblastoma”. Among the 111 articles identified, 13 studies met our inclusion criteria. The majority of reports showed the presence of estrogen and progesterone receptors in astrocytomas. Overall, higher tumor grades were associated with decreased estrogen receptor expression and increased progesterone receptor expression.

  11. Ulipristal acetate, a progesterone receptor modulator for emergency contraception

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    Jadav, Shilpa P.; Parmar, Dinesh M.

    2012-01-01

    Unwanted pregnancy is a global reproductive health problem. Emergency contraception is defined as the use of drug or device after unprotected or underprotected intercourse to prevent an unwanted pregnancy. 1.5 mg of levonorgestrel as a single dose or in two doses with 12 h apart taken within 72 h of unprotected intercourse is the current gold standard emergency contraception regimen. This method is only effective if used as soon as possible after sexual intercourse and before ovulation. A single dose of 30 mg ulipristal acetate, a novel selective progesterone receptor modulator, has recently been proposed for the emergency contraception use up to 120 h of unprotected intercourse with similar side effect profiles as levonorgestrel. Ulipristal acetate could possibly prevent pregnancy when administered in the advanced follicular phase, even if luteinizing hormone levels have already begun to rise, a time when levonorgestrel is no longer effective in inhibiting ovulation. PMID:22629083

  12. [Aspects of progesterone receptor (PR) activity regulation - impact on breast cancer progression].

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    Piasecka, Dominika; Składanowski, Andrzej C; Kordek, Radzisław; Romańska, Hanna M; Sądej, Rafał

    2015-01-01

    Progesterone receptor (PR) and its specific ligand play a key role in development and physiology of mammary gland. The role of PR in initiation and progression of breast carcinoma (BCa) is unquestionable, although molecular mechanism of PR action is complex and not fully understood. It is known that increased risk of breast cancer is associated with progestin-based (synthetic ligands of progesterone) hormonal contraception or hormone replacement therapies. It is estimated that ER/PR-positive tumours represent approximately 50-70% of all BCa cases, and the loss of PR is associated with resistance to hormonal therapy and increased tumour invasiveness. In classical, genomic signalling pathway cytoplasmic PR, following ligand binding, translocates to the nucleus and regulates expression of genes with the PRE sequence. PR is also involved in a large number of alternative, non-genomic signalling cascades, e.g. PR is able to activate MAPK and PI3K/AKT pathways, which leads to regulation of gene expression. The cross-talk between PR and Growth Factors Receptors (GFR) results in progesterone-independent activation of PR as well as PR-regulated GFR expression and activation. Growth factors signalling promotes formation of a pool of hypersensitive PR responsive to even very low ligand concentration. Transcriptional activity of PR as well as its dynamic impact on processes such as cell migration and adhesion are crucial for BCa progression. Further studies of multifaceted mechanisms of PR action may contribute to new PR-targeting therapeutic strategies for breast cancer patients.

  13. Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

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    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.

  14. Estrogen and progesterone receptor testing in breast carcinoma: concordance of results between local and reference laboratories in Brazil

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    Sheila Cristina Lordelo Wludarski

    Full Text Available CONTEXT AND OBJECTIVE: Breast cancer accounts for approximately one quarter of all cancers in females. Estrogen and progesterone receptor testing has become an essential part of the clinical evaluation of breast carcinoma patients, and accurate results are critical in identifying patients who may benefit from hormone therapy. The present study had the aim of investigating the concordance of the results from hormone receptor tests between a reference laboratory and local (or community laboratories in Brazil. DESIGN AND SETTING: Retrospective study at a reference pathology laboratory. METHODS: The concordance in the results from hormone receptor tests between a reference laboratory and 146 local laboratories in Brazil was compared in relation to 500 invasive breast carcinoma cases, using immunohistochemistry. RESULTS: There was concordance in 89.4% (447/500 cases and 85.0% (425/500 cases of the results from estrogen (κ = 0.744, P < 0.001 and progesterone (κ = 0.688, P < 0.001 receptor tests, respectively, between local and reference laboratories. This was similar to findings in other countries. The false negative rates from estrogen and progesterone receptor tests in local laboratories were 8.7% and 14.4%, respectively. The false positive rates from estrogen and progesterone receptor tests in local laboratories were 15.5% and 16.0%, respectively. CONCLUSION: Technical and result interpretation issues may explain most of the discordances in hormone receptor testing in local laboratories. Validation of estrogen and progesterone receptor tests at local laboratories, with rigorous quality control measures, is strongly recommended in order to avoid erroneous treatment of breast cancer patients.

  15. Sensorimotor development in neonatal progesterone receptor knockout mice.

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    Willing, Jari; Wagner, Christine K

    2014-01-01

    Early exposure to steroid hormones can permanently and dramatically alter neural development. This is best understood in the organizational effects of hormones during development of brain regions involved in reproductive behaviors or neuroendocrine function. However, recent evidence strongly suggests that steroid hormones play a vital role in shaping brain regions involved in cognitive behavior such as the cerebral cortex. The most abundantly expressed steroid hormone receptor in the developing rodent cortex is the progesterone receptor (PR). In the rat, PR is initially expressed in the developmentally-critical subplate at E18, and subsequently in laminas V and II/III through the first three postnatal weeks (Quadros et al. [2007] J Comp Neurol 504:42-56; Lopez & Wagner [2009]: J Comp Neurol 512:124-139), coinciding with significant periods of dendritic maturation, the arrival of afferents and synaptogenesis. In the present study, we investigated PR expression in the neonatal mouse somatosensory cortex. Additionally, to investigate the potential role of PR in developing cortex, we examined sensorimotor function in the first two postnatal weeks in PR knockout mice and their wildtype (WT) and heterozygous (HZ) counterparts. While the three genotypes were similar in most regards, PRKO and HZ mice lost the rooting reflex 2-3 days earlier than WT mice. These studies represent the first developmental behavioral assessment of PRKO mice and suggest PR expression may play an important role in the maturation of cortical connectivity and sensorimotor integration. Copyright © 2013 Wiley Periodicals, Inc.

  16. The Role of Progesterone and a Novel Progesterone Receptor, Progesterone Receptor Membrane Component 1, in the Inflammatory Response of Fetal Membranes to Ureaplasma parvum Infection.

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    Liping Feng

    Full Text Available Ureaplasma parvum (U. parvum is gaining recognition as an important pathogen for chorioamnionitis and preterm premature rupture of membranes. We aimed to investigate the roles of progesterone (P4 and a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1, in the response of fetal membranes to U. parvum. Fetal membrane cells (amnion, chorion and decidua were isolated and confirmed to be free of Mycoplasmataceae. Cells were treated with U. parvum (5x106 CFU, and adherence was quantified by qPCR. Amnion and chorion cells were transfected with scrambled siRNA or validated PGRMC1 siRNA for 72h. Cells were then treated with U. parvum for 4h with or without pretreatment with P4 (10-7 M or ethanol for 1h. Interleukin-8 (IL-8, matrix metalloproteinase 9 (MMP9 and cyclooxygenase (COX-2 mRNA expression were quantified by qRT-PCR. Culture medium was harvested and analyzed for IL-8 and prostaglandin (PGE2 secretion by ELISA and MMP9 activity by zymography. U. parvum had a mean adherence of 15.0±0.6%, 16.9± 3.7% and 4.7±0.3% in cultured amnion, chorion and decidua cells, respectively. Exposure to U. parvum elicited significant inflammatory responses including induction of IL-8, COX-2, PGE2 and MMP9. A possible role of PGRMC1 was identified in the inhibition of U. parvum-stimulated COX-2 and MMP9 mRNA expression in chorion cells and MMP9 activity in amnion cells. On the other hand, it might enhance the U. parvum-stimulated IL-8 protein secretion in amnion cells. P4, mediated through PGRMC1, significantly inhibited U. Parvum-induced MMP9 mRNA and COX-2 mRNA expression in chorion cells. P4 appeared to attenuate U. parvum induced IL-8 mRNA expression in chorion cells, but this P4 effect might not mediated through PGRMC1. In summary, U. parvum preferentially adheres to and induces inflammatory responses in chorion and amnion cells. P4 and PGRMC1 appear to differentially modulate the inflammatory responses induced by U. parvum among

  17. Cloning and initial characterization of nuclear and membrane progesterone receptors in the Fathead Minnow, Pimephales promelas

    Science.gov (United States)

    Both native progestagens and synthetic progestins have important effects on reproduction that are mediated through progesterone receptors (PRs). They regulate gamete maturation and can serve as precursors for other steroid hormones in vertebrates and act as reproductive pheromone...

  18. Endometrial Effects of Prolonged Therapy with the Selective Progesterone Receptor Modulator Ulipristal Acetate: A Case Report.

    Science.gov (United States)

    Levy, Gary; Elkas, John; Armstrong, Alicia Y; Nieman, Lynnette K

    2016-01-01

    Prolonged exposure to a selective progesterone receptor modulator (ulipristal acetate) in a patient with benign metastasizing leiomyoma did not result in endometrial hyperplasia or neoplasia. A woman with history of benign metastasizing leiomyoma underwent medical treatment for 5 years with ulipristal acetate. Endometrial biopsies were performed at established intervals to monitor for intraepithelial neoplasia or progesterone receptor modulator-associated endometrial changes (PAECs). The patient tolerated UPA therapy well; there was no evidence of hyperplasia or proliferative changes associated with progesterone-associated endometrial changes. In this case prolonged exposure to ulipristal acetate did not result in premalignant or malignant endometrial pathology.

  19. Vaginal ring delivery of selective progesterone receptor modulators for contraception

    Science.gov (United States)

    Jensen, Jeffrey T.

    2013-01-01

    Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) are under development to address limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing, and therefore might improve the effectiveness of contraception. The principle contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1–2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6–7 ng/mL. PMID:23040126

  20. Bone growth and turnover in progesterone receptor knockout mice.

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    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jaime C.; Waters, Katrina M.; Lydon, John P.; O' Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    2008-05-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bones of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.

  1. Immunolocalization of progesterone receptors in binucleate trophoblast cells of the buffalo placenta (Bubalus bubalis

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    Carlos Eduardo Ambrósio

    2007-06-01

    Full Text Available The binucleate trophoblast cells (CTBs of the water buffalo placenta (Bubalus bubalis were studied with emphasis on the presence of progesterone receptor. Placentomal tissues from 27 buffalos (2-10 months of pregnancy were processed and embedded in paraplast (Paraplast Embedding Media – Paraplast Plus to locate the progesterone receptors using the immunohistochemistry technique. The immunohistochemical reaction for progesterone receptor through monoclonal antibody PgR Ab2 showed staining of CTBs, caruncular epithelial and estromal cells and blood vessel estromal pericitos present in the placentome throughout the entire gestational period analyzed. These results indicate the production of progesterone with autocrine and paracrine action in the placentome growth, differentiation and functional regulation.

  2. Membrane progesterone receptor beta (mPRβ/Paqr8) promotes progesterone-dependent neurite outgrowth in PC12 neuronal cells via non-G protein-coupled receptor (GPCR) signaling.

    Science.gov (United States)

    Kasubuchi, Mayu; Watanabe, Keita; Hirano, Kanako; Inoue, Daisuke; Li, Xuan; Terasawa, Kazuya; Konishi, Morichika; Itoh, Nobuyuki; Kimura, Ikuo

    2017-07-12

    Recently, sex steroid membrane receptors garnered world-wide attention because they may be related to sex hormone-mediated unknown rapid non-genomic action that cannot be currently explained by their genomic action via nuclear receptors. Progesterone affects cell proliferation and survival via non-genomic effects. In this process, membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ, and mPRε) were identified as putative G protein-coupled receptors (GPCRs) for progesterone. However, the structure, intracellular signaling, and physiological functions of these progesterone receptors are still unclear. Here, we identify a molecular mechanism by which progesterone promotes neurite outgrowth through mPRβ (Paqr8) activation. Mouse mPRβ mRNA was specifically expressed in the central nervous system. It has an incomplete GPCR topology, presenting 6 transmembrane domains and did not exhibit typical GPCR signaling. Progesterone-dependent neurite outgrowth was exhibited by the promotion of ERK phosphorylation via mPRβ, but not via other progesterone receptors such as progesterone membrane receptor 1 (PGRMC-1) and nuclear progesterone receptor in nerve growth factor-induced neuronal PC12 cells. These findings provide new insights of regarding the non-genomic action of progesterone in the central nervous system.

  3. 17β-estradiol and progesterone effect on human papillomavirus 16 positive cells grown as spheroid co-cultures.

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    Ruutu, Merja; Rautava, Jaana; Turunen, Aaro; Tirri, Teemu; Syrjänen, Stina

    2017-10-05

    Human papillomavirus (HPV) is the key epidemiologic factor of cervical cancer, but additional cofactors are mandatory. Estrogen has been considered as one of those. Here, the aim was to study the effects of steroid hormones on HPV16 E6-E7, estradiol receptors ERα and ERβ, and progesterone receptor (PR) in HPV16-positive cervical carcinoma cell lines SiHa and CaSki grown as epithelial and fibroblast spheroid co-cultures. The spheroid co-cultures were exposured to 17β-estradiol or progesterone from day 7 onwards. mRNA levels of HPV16 E6-E7, ERα, ERβ and PR normalized against GAPDH were analyzed with quantitative reverse transcription-qPCR (RT-qPCR). 17β-estradiol and progesterone decreased HPV16 E6-E7 mRNA expression in CaSki and increased in SiHA co-cultures. In CaSki co-cultures, ERβ expression was blocked after 17β-estradiol exposure while in SiHa cells it slightly increased ERβ expression. PR expression was seen only in CaSki spheroids and it vanished after exposure to steroid hormones. Fibroblasts expressed all three hormone receptors as monolayers but ERβ expression decreased and ERα and PR vanished after co-culturing. Cell culturing platform changes both oncogene and hormone receptor expression in HPV16 positive cervical cancer cell lines. This needs to be considered when in vitro results are extrapolated to in vivo situations.

  4. Detection of oestrogen and progesterone receptor expression in breast tumors by semiquantitative PCR.

    Science.gov (United States)

    Hackl, T; Zickl, M; Dobianer, K; Hruza, C; Czerwenka, K; Spona, J

    1998-01-01

    Estimation of oestrogen receptors (ER) and progesterone receptors (PgR) by dextran-coated charcoal (DCC) or immunohistochemical methods have become standard practices in the management of breast cancer. A "multiplex" polymerase chain reaction (PCR) system was developed for quantitative estimation of ER and PgR mRNA in breast tumour specimens. A statistically significant correlation could be found between the mRNA of the oestrogen and the progesterone receptor (p < or = 0.0001). Protein data defined in classes, compared with mRNA data showed a significant correlation for the oestrogen receptor (p < or = 0.0001) as well as for the progesterone receptor (p < or = 0.046). Messenger RNA could be determined by the present PCR system in tumours assayed as negative by DCC method. Therefore, this sensitive PCR procedure, which requires small amounts of material may be very useful as a diagnostic test to determine the choice of therapy.

  5. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.

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    Yellon, Steven M; Dobyns, Abigail E; Beck, Hailey L; Kurtzman, James T; Garfield, Robert E; Kirby, Michael A

    2013-01-01

    A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone), or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.

  6. Protective actions of progesterone in the cardiovascular system: potential role of membrane progesterone receptors (mPRs) in mediating rapid effects.

    Science.gov (United States)

    Thomas, Peter; Pang, Yefei

    2013-06-01

    The protective functions of progesterone in the cardiovascular system have received little attention even though evidence has accumulated that progesterone lowers blood pressure, inhibits coronary hyperactivity and has powerful vasodilatory and natriuretic effects. One possible reason why potential beneficial actions of progesterone on cardiovascular functions have not been extensively studied is that divergent effects to those of progesterone have been observed in many clinical trials with synthetic progestins such as medroxyprogesterone acetate which are associated with increased risk of coronary disease. Evidence that progesterone exerts protective effects on cardiovascular functions is briefly reviewed. The finding that progesterone administration decreases blood vessel vasoconstriction in several animal models within a few minutes suggests that rapid, nongenomic progesterone mechanisms are of physiological importance in regulating vascular tone. Rapid activation of second messenger pathways by progesterone has been observed in vascular endothelial and smooth muscle cells, resulting in alterations in endothelial nitric oxide synthase (eNOS) activity and calcium influx, respectively. Both nuclear progesterone receptors (PRs) and novel membrane progesterone receptors (mPRs) are candidates for the intermediaries in these rapid, cell-surface initiated progesterone actions in endothelial and smooth muscle vascular cells. PRs have been detected in both cell types. New data are presented showing mPRα, mPRβ and mPRγ are also present in human endothelial and smooth muscle vascular cells. Preliminary evidence suggests mPRs mediate rapid progestin signaling in these endothelial cells, resulting in down-regulation of cAMP production and increased nitric oxide synthesis. The role of mPRs in progesterone regulation of cardiovascular functions warrants further investigation. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Safety of treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate.

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    Donnez, Jacques; Donnez, Olivier; Dolmans, Marie-Madeleine

    2016-12-01

    During the last decade, there has been increased emphasis on the role of progesterone in the promotion of fibroid growth, as well as heightened interest in modulating progesterone pathways by use of selective progesterone receptor modulators (SPRMs). Among them, ulipristal acetate (UPA) has proved its efficacy in the management of symptomatic myomas by controlling bleeding and inducing amenorrhea, and reducing the size of myomas in the majority of cases. Areas covered: In this review, we summarize published scientific studies exploring evidence of the safety of SPRMs and particularly UPA, a drug approved for the management of symptomatic uterine fibroids. We focus essentially on endometrial changes induced by UPA, and also evaluate other safety outcomes. Expert opinion: Data from published reports of randomized controlled trials (RCTs) over 5 years have demonstrated that UPA does indeed induce endometrial changes (known as progesterone receptor modulator-associated endometrial changes), but they have been shown to be both benign and reversible.

  8. Recent advances in structure of progestins and their binding to progesterone receptors.

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    Cabeza, Marisa; Heuze, Yvonne; Sánchez, Araceli; Garrido, Mariana; Bratoeff, Eugene

    2015-02-01

    The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.

  9. Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium

    Science.gov (United States)

    Whitaker, L.H.R.; Murray, A.A.; Matthews, R.; Shaw, G.; Williams, A.R.W.; Saunders, P.T.K.

    2017-01-01

    Abstract STUDY QUESTION What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. STUDY DESIGN SIZE, DURATION Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9–12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38–52 with fibroids were derived from institutional tissue archives. PARTICIPANTS/MATERIALS, SETTING, METHODS Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. MAIN RESULTS AND THE ROLE OF CHANCE UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase

  10. In-vitro study of gonadotrophin signaling pathways in human granulosa cells in relation to progesterone receptor expression.

    Science.gov (United States)

    Henríquez, Soledad; Kohen, Paulina; Muñoz, Alex; Godoy, Ana; Orge, Felipe; Strauss, Jerome F; Devoto, Luigi

    2017-10-01

    In humans, data on gonadotrophin-activated (LH, HCG and FSH) progesterone receptor expression and signalling pathways involved in matrix metalloproteinases (MMPs) expression presumably linked to the follicle rupture, are limited. Our hypothesis is LH, HCG and FSH increase progesterone receptor expression in granulosa cells through different signalling pathways, leading to an increased expression of ADAMTS-1 and MMP3/10, which may mediate follicular rupture through the transcription factor, HIF1A. Human granulosa cells were isolated from follicular aspirates obtained from 22 healthy women participating in our IVF programme for male-factor infertility. Progesterone receptor and HIF1A expression was assessed by immunofluorescence, and PKA-PKC-PI3K- ERK1/2, ADAMTS-1 and MMP3/10 expression by Western blot in pre-ovulatory and in cultured granulosa cells. Results show that HCG, LH and FSH regulate progesterone receptor expression and activate PKA, PKC, PI3K and ERK1/2 signalling pathways in granulosa cells but progesterone receptor expression is only mediated by PKA, PKC and ERK pathways. HCG, FSH and LH regulated MMPs expression through progesterone receptors. Moreover, HCG-progesterone-receptor-dependent HIF1A expression stimulated MMP3/10 expression but not that of ADAMTS-1. These results suggest differential downstream progesterone receptor signalling, as progesterone receptor regulates MMP3/10 expression via HIF1A, which is not involved in ADAMTS-1 expression. Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  11. Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives

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    Kloosterboer, H.J.; Vonk-Noordegraaf, C.A.; Turpijn, E.W.

    1988-09-01

    The relative binding affinities (RBAs) of four progestational compounds (norethisterone, levonorgestrel, 3-keto-desogestrel and gestodene) for the human progesterone and androgen receptors were measured in MCF-7 cytosol and intact MCF-7 cells. For the binding to the progesterone receptor, both Org 2058 and Org 3236 (or 3-keto-desogestrel) were used as labelled ligands. The following ranking (low to high) for the RBA of the nuclear (intact cells) progesterone receptor irrespective of the ligand used is found: norethisterone much less than levonorgestrel less than 3-keto-destogestrel less than gestodene. The difference between the various progestagens is significant with the exception of that between 3-keto-desogestrel and gestodene, when Org 2058 is used as ligand. For the cytosolic progesterone receptor, the same order is found with the exception that similar RBAs are found for gestodene and 3-keto-desogestrel. The four progestagens clearly differ with respect to binding to the androgen receptor using dihydrotestosterone as labelled ligand in intact cells; the ranking (low to high) is: norethisterone less than 3 keto-desogestrel less than levonorgestrel and gestodene. The difference between 3-keto-desogestrel and levonorgestrel or gestodene is significant. The selectivity indices (ratio of the mean RBA for the progesterone receptor to that of androgen receptor) in intact cells are significantly higher for 3-keto-desogestrel and gestodene than for levonorgestrel and norethisterone. From these results we conclude that the introduction of the 18-methyl in norethisterone (levonorgestel) increases both the binding to the progesterone and androgen receptors.

  12. The Biology of Progesterone Receptor in the Normal Mammary gland and in Breast Cancer

    Science.gov (United States)

    Obr, Alison; Edwards, Dean P.

    2011-01-01

    This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor of activated nuclear factor κ ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression. PMID:22193050

  13. G-protein coupled progesterone receptors in the plasma membrane of fungus Rhizopus nigricans.

    Science.gov (United States)

    Bavec, A; Slajpah, M; Lenasi, H; Yorko, M; Breskvar, K

    2000-01-01

    We have demonstrated simultaneous existence of progesterone receptors and GTPase activity in the membranes prepared from the filamentous fungus Rhizopus nigricans. The results obtained with pertussis toxin treated fungal mycelium suggest that these receptors do not couple to Gi-Go-proteins and play a role in the induction of steroid hydroxylating enzyme system by steroid substrates in the fungus.

  14. Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

    Science.gov (United States)

    Lusher, Scott J.; Raaijmakers, Hans C. A.; Vu-Pham, Diep; Dechering, Koen; Lam, Tsang Wai; Brown, Angus R.; Hamilton, Niall M.; Nimz, Olaf; Bosch, Rolien; McGuire, Ross; Oubrie, Arthur; de Vlieg, Jacob

    2011-01-01

    The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes. PMID:21849509

  15. Specific interactions of steroids, arylhydrocarbons and flavonoids with progesterone receptors from the cytosol of the fungus Rhizopus nigricans.

    Science.gov (United States)

    Lenasi, Helena; Breskvar, Katja

    2004-08-01

    Rhizopus nigricans (R. nigricans) transforms fungitoxic progesterone into the less toxic 11alpha-hydroxyprogesterone which is then able to exit the mycelia into the surrounding water. Hydroxylation of progesterone is an inducible process in which cytosolic progesterone receptors could be involved. In the present study, we characterised receptors with respect to ligand specificity and to their involvement in progesterone induction of hydroxylase. EC(50) values of different ligands (steroids, xenobiotic arylhydrocarbons and natural flavonoids) were determined by competition studies using 40nM ((3)H)progesterone. C21 and C19 3-oxo-4-ene steroids were good competitors (EC(50) of progesterone 2.3 +/- 0.1 x 10(-7)M, EC(50) of androsten-3,17-dione 24 +/- 2 x 10(-7)M). The presence of hydroxyl groups in steroids significantly decreased the affinity for receptors. The arylhydrocarbons alpha-naphthoflavone and ketoconazole exhibited EC(50) values of 0.3 +/- 0.01 x 10(-7)M and 27 +/- 5 x 10(-7)M, respectively, whereas beta-naphthoflavone and benzo(a)pyrene were not able to displace labelled progesterone completely. The competition curves obtained by natural flavonoids also did not reach the bottom level of non-labelled progesterone, indicating the interaction at some allosteric binding site(s) of progesterone receptors. All ligands were examined for their involvement in progesterone-hydroxylase induction. Steroid agonists induced the enzyme in a dose-dependent manner in accordance with their affinity for receptors, whereas arylhydrocarbons and natural flavonoids did not induce the enzyme. The agonistic action of steroids, together with the antagonistic action of alpha-naphthoflavone, strongly suggests the involvement of progesterone receptors in progesterone signalling resulting in the induction of progesterone-hydroxylase.

  16. Expression of oxytocin, progesterone, and estrogen receptors in the reproductive tract of bitches with pyometra.

    Science.gov (United States)

    Prapaiwan, N; Manee-In, S; Olanratmanee, E; Srisuwatanasagul, S

    2017-02-01

    Canine pyometra is considered a serious and life-threatening condition. Due to the relationship among sex steroid hormones, oxytocin receptor (OTR) expression, and canine pyometra pathogenesis, this study aimed to investigate the expression of oxytocin, progesterone, and estrogen receptors in the reproductive tissues of canines with pyometra by real-time PCR and immunohistochemistry. A total of 27 pyometra bitches were classified into open- and closed-cervix pyometra groups based on the presence of vaginal discharge. Moreover, 15 normal bitches in the luteal phase served as a control group. The results showed that OTR gene expression in the ovary of pyometra bitches was higher than that of normal bitches, whereas the level of OTR gene expression in the cervix of pyometra bitches was less than that of normal bitches (P pyometra bitches compared with normal bitches, whereas a higher percentage of OTR-positive immunostaining in uteri and cervices were found in pyometra bitches compared with normal bitches (P pyometra bitches were less than that of normal bitches (P pyometra bitches was not different. Our findings suggest that pyometra pathogenesis is associated with a change in expression of OTR and sex steroid receptors in the canine reproductive tract. However, cervical dilation in bitches with pyometra was not influenced by the expression of OTR and sex steroid receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Progesterone receptor modulates estrogen receptor-α action in breast cancer

    Science.gov (United States)

    Mohammed, Hisham; Russell, I. Alasdair; Stark, Rory; Rueda, Oscar M.; Hickey, Theresa E.; Tarulli, Gerard A.; Serandour, Aurelien A. A.; Birrell, Stephen N.; Bruna, Alejandra; Saadi, Amel; Menon, Suraj; Hadfield, James; Pugh, Michelle; Raj, Ganesh V.; Brown, Gordon D.; D’Santos, Clive; Robinson, Jessica L. L.; Silva, Grace; Launchbury, Rosalind; Perou, Charles M.; Stingl, John; Caldas, Carlos; Tilley, Wayne D.; Carroll, Jason S.

    2015-01-01

    Summary Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions. PMID:26153859

  18. Stress-induced progesterone secretion and progesterone receptor immunoreactivity in the paraventricular nucleus are modulated by pubertal development in male rats.

    Science.gov (United States)

    Romeo, Russell D; Bellani, Rudy; McEwen, Bruce S

    2005-12-01

    Male rats show a differential adrenocortical response to stress before and after pubertal development, such that prepubertal animals have a more prolonged stress-induced corticosterone response compared to adults. Whether pubertal maturation affects other adrenocortical responses to stress is currently unknown. To address this question, we assessed stress-induced progesterone secretion in both intact and gonadectomized prepubertal (28 days of age) and adult (77 days of age) male rats either before or after exposure to a 30 min session of restraint stress. We found that prepubertal males show a greater and more prolonged stress-induced progesterone response compared to adults. We also found a similar effect in castrated prepubertal and adult males, indicating the differential stress-induced progesterone response is not gonadal in origin. We also examined progesterone receptor (PR) levels by immunohistochemistry in the paraventricular nucleus (PVN) of the hypothalamus, a key regulatory nucleus of the hypothalamic-pituitary-adrenal (HPA) axis, and found lower PR protein expression in the PVN of prepubertal compared to adult males. These data indicate that in addition to corticosterone, stress-induced adrenocortical progesterone levels are differentially affected by pubertal maturation. Furthermore, these data raise the possibility of different progesterone sensitivity of the PVN before and after puberty. The significance of this differential response is presently unknown. However, given the pleiotropic effects of progesterone on male physiology and behaviour, it is likely that the disparate post-stress exposure to progesterone affects the prepubertal and adult male differently.

  19. Mineralocorticoid receptor haplotype, estradiol, progesterone and emotional information processing.

    Science.gov (United States)

    Hamstra, Danielle A; de Kloet, E Ronald; Quataert, Ina; Jansen, Myrthe; Van der Does, Willem

    2017-02-01

    Carriers of MR-haplotype 1 and 3 (GA/CG; rs5522 and rs2070951) are more sensitive to the influence of oral contraceptives (OC) and menstrual cycle phase on emotional information processing than MR-haplotype 2 (CA) carriers. We investigated whether this effect is associated with estradiol (E2) and/or progesterone (P4) levels. Healthy MR-genotyped premenopausal women were tested twice in a counterbalanced design. Naturally cycling (NC) women were tested in the early-follicular and mid-luteal phase and OC-users during OC-intake and in the pill-free week. At both sessions E2 and P4 were assessed in saliva. Tests included implicit and explicit positive and negative affect, attentional blink accuracy, emotional memory, emotion recognition, and risky decision-making (gambling). MR-haplotype 2 homozygotes had higher implicit happiness scores than MR-haplotype 2 heterozygotes (p=0.031) and MR-haplotype 1/3 carriers (p<0.001). MR-haplotype 2 homozygotes also had longer reaction times to happy faces in an emotion recognition test than MR-haplotype 1/3 (p=0.001). Practice effects were observed for most measures. The pattern of correlations between information processing and P4 or E2 differed between sessions, as well as the moderating effects of the MR genotype. In the first session the MR-genotype moderated the influence of P4 on implicit anxiety (sr=-0.30; p=0.005): higher P4 was associated with reduction in implicit anxiety, but only in MR-haplotype 2 homozygotes (sr=-0.61; p=0.012). In the second session the MR-genotype moderated the influence of E2 on the recognition of facial expressions of happiness (sr=-0.21; p=0.035): only in MR-haplotype 1/3 higher E2 was correlated with happiness recognition (sr=0.29; p=0.005). In the second session higher E2 and P4 were negatively correlated with accuracy in lag2 trials of the attentional blink task (p<0.001). Thus NC women, compared to OC-users, performed worse on lag 2 trials (p=0.041). The higher implicit happiness scores of MR

  20. The neurosteroid progesterone underlies estrogen positive feedback of the LH surge

    Directory of Open Access Journals (Sweden)

    Paul E Micevych

    2011-12-01

    Full Text Available Our understanding the steroid regulation of neural function has rapidly evolved in the past decades. Not long ago the prevailing thoughts were that peripheral steroid hormones carried information to the brain which passively responded to these steroids. These steroid actions were slow, taking hours to days to be realized because they regulated gene expression. Over the past three decades, discoveries of new steroid receptors, rapid membrane initiated signaling mechanisms and de novo neurosteroidogenesis have shed new light on the complexity of steroids actions within the nervous system. Sexual differentiation of the brain during development occurs predominately through timed steroid-mediated expression of proteins and long term epigenetic modifications. In contrast across the estrous cycle, estradiol release from developing ovarian follicles initially increases slowly and then at proestrus increases rapidly. This pattern of estradiol release acts through both classical genomic mechanisms and rapid membrane-initiated signaling in the brain to coordinate reproductive behavior and physiology. This review focuses on recently discovered estrogen receptor- (ER membrane signaling mechanisms that estradiol utilizes during estrogen positive feedback to stimulate de novo progesterone synthesis within the hypothalamus to trigger the luteinizing hormone surge important for ovulation and estrous cyclicity. The activation of these signaling pathways appears to be coordinated by the rising and waning of estradiol throughout the estrous cycle and integral to the negative and positive feedback mechanisms of estradiol. This differential responsiveness is part of the timing mechanism triggering the luteinizing hormone surge.

  1. Progesterone treatment shows greater protection in brain vs. retina in a rat model of middle cerebral artery occlusion: Progesterone receptor levels may play an important role.

    Science.gov (United States)

    Allen, Rachael S; Sayeed, Iqbal; Oumarbaeva, Yuliya; Morrison, Katherine C; Choi, Paul H; Pardue, Machelle T; Stein, Donald G

    2016-11-22

    To determine whether inflammation increases in retina as it does in brain following middle cerebral artery occlusion (MCAO), and whether the neurosteroid progesterone, shown to have protective effects in both retina and brain after MCAO, reduces inflammation in retina as well as brain. MCAO rats treated systemically with progesterone or vehicle were compared with shams. Protein levels of cytosolic NF-κB, nuclear NF-κB, phosphorylated NF-κB, IL-6, TNF-α, CD11b, progesterone receptor A and B, and pregnane X receptor were assessed in retinas and brains at 24 and 48 h using western blots. Following MCAO, significant increases were observed in the following inflammatory markers: pNF-κB and CD11b at 24 h in both brain and retina, nuclear NF-κB at 24 h in brain and 48 h in retina, and TNF-α at 24 h in brain.Progesterone treatment in MCAO animals significantly attenuated levels of the following markers in brain: pNF-κB, nuclear NF-κB, IL-6, TNF-α, and CD11b, with significantly increased levels of cytosolic NF-κB. Retinas from progesterone-treated animals showed significantly reduced levels of nuclear NF-κB and IL-6 and increased levels of cytosolic NF-κB, with a trend for reduction in other markers. Post-MCAO, progesterone receptors A and B were upregulated in brain and downregulated in retina. Inflammatory markers increased in both brain and retina after MCAO, with greater increases observed in brain. Progesterone treatment reduced inflammation, with more dramatic reductions observed in brain than retina. This differential effect may be due to differences in the response of progesterone receptors in brain and retina after injury.

  2. Effect of mifepristone on steroid receptor expression and biotransformation of oestrogen and progesterone in rat uterus and deciduoma.

    Science.gov (United States)

    Vij, Urmila; Kumar, Anand; Sharma, Kanhaiya; Kaushal, Mishi; Mehra, Raj

    2006-01-01

    [corrected] Mifepristone is a synthetic antiprogestin which terminates early pregnancy. Since it interferes with the progesterone maintained decidua, we compared the effect of mifepristone on oestrogen and progesterone receptors, and on the biotransformation of these hormones in normal and deciduous uterus. Ovariectomized rats were treated with an oestrogen-progesterone hormone regimen and deciduoma was induced by trauma in one horn of the rat uterus while the other served as a control under an identical hormonal milieu. Hormone receptor and biotransformation studies were done using radiolabelled oestradiol and progesterone with high specific activity. The artificially formed decidual tissue was comparable with that of early pregnancy. Mifepristone replenished oestrogen and progesterone receptors which were suppressed by progesterone in both the normal and decidualized uterine horns. Inhibition of oestrogen receptors by progesterone correlated with decreased oestradiol levels at the site of action. Metabolism of progesterone to less potent compounds was promoted by mifepristone. The enzymatic activities of 17beta-hydroxysteroid dehydrogenase (which metabolizes oestradiol), and 20alpha-hydroxysteroid dehydrogenase and 5alpha-reductase (which metabolize progesterone) were altered by mifepristone. The effect of mifepristone in varying the hormone receptor population and the availability of different levels of active metabolites of ovarian hormones have an Important role in the antiprogestin action of mifepristone.

  3. The relationship of cerb B 2 expression with estrogen receptor and progesterone receptor and prognostic parameters in endometrial carcinomas

    Directory of Open Access Journals (Sweden)

    Kandemir Nilufer

    2010-02-01

    Full Text Available Abstract Background Endometrial carcinoma (EC is the most common malignancy of the female genital tract. Gene alterations and overexpression of various oncogenes are important in tumor development. The human HER 2 neu (c-erbB-2 gene product is a transmembrane receptor with an intracellular tyrosine kinase that plays an important role in coordinating the endometrial growth factor receptor signaling network. The aim of this study was to investigate the expression of c-erbB-2 in endometrial cancer, to study its correlation to established prognostic parameters and estrogen receptor (ER and progesterone receptor (PR status. Methods Immunohistochemical (IHC analyses of ER, PR and c-erbB-2 were performed in 72 EC cases. Results We detected a positive staining with c erbB 2 in 18.1% of the cases and determined a statistically significant relation between c-erbB-2 and PR. We could not find a statistically significant relation between c-erbB-2 staining and ER. There was not a statistically significant difference between c-erbB-2 and histological grade. The highest level of c-erbB-2 was found in grade 2 cases. There was not any statistically significant relation between c-erbB-2 and menstrual status, myometrial invasion, lymph node status, stage and survival. Conclusions Although our study provides additional evidence of the potential prognostic role of c-erbB-2, further prospective and controlled studies are required to validate their clinical usefulness.

  4. Membrane progesterone receptor beta (mPR?/Paqr8) promotes progesterone-dependent neurite outgrowth in PC12 neuronal cells via non-G protein-coupled receptor (GPCR) signaling

    OpenAIRE

    Kasubuchi, Mayu; Watanabe, Keita; Hirano, Kanako; Inoue, Daisuke; Li, Xuan; Terasawa, Kazuya; Konishi, Morichika; Itoh, Nobuyuki; Kimura, Ikuo

    2017-01-01

    Recently, sex steroid membrane receptors garnered world-wide attention because they may be related to sex hormone-mediated unknown rapid non-genomic action that cannot be currently explained by their genomic action via nuclear receptors. Progesterone affects cell proliferation and survival via non-genomic effects. In this process, membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ, and mPRε) were identified as putative G protein-coupled receptors (GPCRs) for progesterone. However, the st...

  5. [Estrogen and progesterone receptors in non carcinomatous breast diseases (author's transl)].

    Science.gov (United States)

    May-Levin, F; Contesso, G; Guerinot, F; Delarue, J C; Bohuon, C

    1977-04-01

    Cytosolic receptors for estrogens and progesterone are studied using an exchange method in various types of benign breast diseases: fibroadenomas, fibrocystic mastosis, phylloid tumors and gynecomastias. The results show clearly that, contrary to breast carcinomas, receptors are generally not present in benign tumors. These results are statistically significant for all the women studied. Studying the pathological aspects of the tumors, it can be noted that the presence of receptors, is correlated with proliferation forms with large epithelial components. Furthermore, these results show that receptors are not found in gynecomastia. In conclusion, the physician should follow up very carefully the patients with a benign tumor, when hormono-receptors are present.

  6. MECHANISMS RESPONSIBLE FOR PROGESTERONE’S PROTECTION AGAINST LORDOSIS-INHIBITING EFFECTS OF RESTRAINT I. ROLE OF PROGESTERONE RECEPTORS

    Science.gov (United States)

    Hassell, James; Miryala, Chandra Suma Johnson; Hiegel, Cindy

    2011-01-01

    Progestins and antiprogestins are widely used therapeutic agents in humans. In many cases, these are indicated for the treatment of reproductive activites. However, progesterone has widespread physiological effects including a reduction of the response to stress. We have reported that 5 min of restraint reduced lordosis behavior of ovariectomized rats hormonally primed with estradiol benzoate. When ovariectomized rats received both estradiol benzoate and progesterone priming, restraint had minimal effects on lordosis. Progesterone influences behavior through classical intracellular progesterone receptor-mediated nuclear events as well as extranuclear events. How these multiple events contribute to the response to stress are unclear. The current project was designed to initiate examination of the mechanisms responsible for progesterone’s ability to protect against the effects of the restraint. In the first experiment, ovariectomized rats, primed with 10 µg estradiol benzoate, received 500 µg progesterone 4 hr, 1 hr, or 30 min before restraint. When progesterone was injected 4 hr before restraint, progesterone eliminated the effects of restraint. In contrast, progesterone 30 min before restraint offered no protection. Effects of progesterone 1 hr before restraint were equivocal allowing the suggestion that less than 4 hr of progesterone priming might be sufficient. In the second experiment, the synthetic progestin, medroxyprogesterone, was shown to mimic effects of progesterone in preventing effects of restraint. Finally, the progesterone receptor antagonist, RU486, attenuated progesterone’s protection against restraint. These findings offer evidence that ligand-activated progesterone receptor mechanisms contribute to the maintenance of lordosis behavior in the presence of mild stress. PMID:21635894

  7. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.

    Directory of Open Access Journals (Sweden)

    Steven M Yellon

    Full Text Available A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone, or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.

  8. A paracrine role for the epithelial progesterone receptor in mammary gland development

    OpenAIRE

    Brisken, Cathrin; Park, Sissela; Vass, Tibor; Lydon, John P.; O’Malley, Bert W.; Weinberg, Robert A.

    1998-01-01

    Recently generated progesterone receptor (PR)-negative (PR−/−) mice provide an excellent model for dissecting the role of progesterone in the development of the mammary gland during puberty and pregnancy. However, the full extent of the mammary gland defect in these mice caused by the absence of the PR cannot be assessed, because PR−/− mice do not exhibit estrous cycles and fail to become pregnant. To circumvent this difficulty, we have transplanted PR−/− breasts into wild-type mice, and we h...

  9. Effects of dexamethasone on progesterone and estrogen profiles and uterine progesterone receptor localization during pregnancy in Sahel goat in Semi-Arid region

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    Dauda Yahi

    2017-05-01

    Full Text Available Abstract Background Despite the widespread use of dexamethasone in veterinary and human medicine, it is reported to cause some severe pregnancy related side effects like abortion in some animals. The mechanism of the response is not clear but seems to be related to interspecies and/or breed difference in response which may involve alterations in the concentrations of some reproductive hormones. Methods Twenty Sahel goats comprising 18 does and 2 bucks were used for this study. Pregnancies were achieved by natural mating after synchronization. Repeated dexamethasone injections were given at 0.25 mg/kg body weight. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested at days 28 and day 78 of gestation through caesarean section for immunohistochemical analysis using 3 pregnant does randomly selected from each group at each instant. Data were expressed as Means ± Standard Deviations and analyzed using statistical soft ware package, GraphPad Instant, version 3.0 (2003 and progesterone receptor (PR were scored semi-quantitatively. Results Dexamethasone treatments had no significant (p > 0.05 effect on progesterone and estrogen concentrations in pregnant Sahel goats but up regulated PR from 2+ to 3+ in second trimester. Conclusion As dexamethasone adverse effect on placenta is an established fact, the lack of effect on progesterone level in this study may be due to the fact that unlike other species whose progesterone production during pregnancy is placenta – dependent, in goats is corpus luteum - dependent. Consequently dexamethasone adverse effect on placenta reported in literatures did not influence progesterone levels during pregnancy in Sahel goat. The up regulation of progesterone receptor (PR in Sahel goat gravid uterus is a beneficial effects and that dexamethasone can safely be used in corpus luteum – dependent progesterone secreting pregnant animal species like Sahel goat and camel. Therefore

  10. Effects of dexamethasone on progesterone and estrogen profiles and uterine progesterone receptor localization during pregnancy in Sahel goat in Semi-Arid region.

    Science.gov (United States)

    Yahi, Dauda; Ojo, Nicholas Adetayo; Mshelia, Gideon Dauda

    2017-01-01

    Despite the widespread use of dexamethasone in veterinary and human medicine, it is reported to cause some severe pregnancy related side effects like abortion in some animals. The mechanism of the response is not clear but seems to be related to interspecies and/or breed difference in response which may involve alterations in the concentrations of some reproductive hormones. Twenty Sahel goats comprising 18 does and 2 bucks were used for this study. Pregnancies were achieved by natural mating after synchronization. Repeated dexamethasone injections were given at 0.25 mg/kg body weight. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested at days 28 and day 78 of gestation through caesarean section for immunohistochemical analysis using 3 pregnant does randomly selected from each group at each instant. Data were expressed as Means ± Standard Deviations and analyzed using statistical soft ware package, GraphPad Instant, version 3.0 (2003) and progesterone receptor (PR) were scored semi-quantitatively. Dexamethasone treatments had no significant (p > 0.05) effect on progesterone and estrogen concentrations in pregnant Sahel goats but up regulated PR from 2+ to 3+ in second trimester. As dexamethasone adverse effect on placenta is an established fact, the lack of effect on progesterone level in this study may be due to the fact that unlike other species whose progesterone production during pregnancy is placenta - dependent, in goats is corpus luteum - dependent. Consequently dexamethasone adverse effect on placenta reported in literatures did not influence progesterone levels during pregnancy in Sahel goat. The up regulation of progesterone receptor (PR) in Sahel goat gravid uterus is a beneficial effects and that dexamethasone can safely be used in corpus luteum - dependent progesterone secreting pregnant animal species like Sahel goat and camel. Therefore source of progesterone secretions during pregnancy should be considered

  11. Immunohistochemical localization of progesterone receptor isoforms and estrogen receptor alpha in the chicken oviduct magnum during development.

    Science.gov (United States)

    González-Morán, María Genoveva

    2015-10-01

    In this work, the immunohistochemical expression of progesterone receptor (PR) isoforms and estrogen receptor alpha (ER-α), as well as the histomorphometric changes of the magnum region of the left oviduct from 8-day-old chicken embryos to one-month-old chickens were evaluated. Results indicate evident histological changes in the oviduct magnum during development mainly in the magnum's mucosa. Immunohistochemical analysis showed that the oviduct magnum from 8-day-old chicken embryos to one-day-old chickens did not present any PR isoform, but the oviduct magnum of one-week and one-month-old chickens expressed PR in the nuclei of all cell types. In epithelial cells, PR-B was the only isoform expressed; in muscle and serosa cells, PR-A isoform was the only isoform expressed; and stromal cells expressed both isoforms. The results also demonstrate positive ER-α immunostaining in the nuclei of different cells from embryonic life to later developmental stages of the oviduct magnum. Data indicate that the variations of ER-α or PR expression or dominance of either PR expression is differentially regulated depending on the cell type, the development of the oviduct, and in an age-specific manner. These variations in sex steroids hormone receptors are related with histological changes of the oviduct magnum through development. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. Primary carcinoid tumor of the kidney with estrogen and progesterone receptor expression

    Science.gov (United States)

    LIN, CHUNHUA; WU, JITAO; GAO, ZHENLI; QU, GUIMEI; WANG, WEI; YU, GUOHUA

    2015-01-01

    Primary carcinoid tumors are uncommon neoplasms in the kidney. The current study presents a case of primary carcinoid tumor of the kidney in a 49-year-old female who suffered from painless gross hematuria for half a month. Left hydronephrosis, a horseshoe kidney and a space-occupying lesion of the left ureter were found by abdominal computed tomography scans and ultrasonic testing. Surgery was performed and an oval tumor was found under the left ureter; the tumor and left kidney were excised completely. The neoplasm was composed of solid nests of cells, trabeculae, adenoid structures and anastomosing cords in a loose and myxoid background. The tumor cells, which were consistent in volume, exhibited centrally oval nuclei with inconspicuous nucleoli, and eosinophilic finely granular cytoplasm. Upon immunohistochemical staining, the neoplastic cells were positive for AE1/AE3, vimentin, synaptophysin, chromogranin A, estrogen receptor and progesterone receptor, while being negative for epithelial membrane antigen, inhibin A, cluster of differentiation (CD)99, S-100 and CD10. Based on the histological characteristics, a diagnosis of primary carcinoid tumor of the left kidney was formed. The patient did not receive further treatment. The total follow-up period was 18 months after the surgery and repeated imaging examinations every 6 months revealed no recurrence. PMID:26171049

  13. Effect of early pregnancy on the expression of progesterone receptor and progesterone-induced blocking factor in ovine lymph node.

    Science.gov (United States)

    Yang, Ling; Zang, Shengqin; Bai, Ying; Yao, Xiaolei; Zhang, Leying

    2017-04-15

    Lymph nodes are the sites where the immune reaction or suppression takes place. Progesterone (P4) exerts an essential effect of the immunomodulation on the maternal uterus during early pregnancy in ruminants. At present study, the inguinal lymph nodes were obtained at day 16 of non-pregnancy, days 13, 16 and 25 of pregnancy (n = 3 for each group) in ewes, and RT-PCR assay, western blot and immunohistochemistry analysis were used to analyze to the effect of early pregnancy on the expression of P4 receptor (PGR) and progesterone-induced blocking factor (PIBF) in the lymph nodes. Our results showed that the PGR and PIBF mRNA were up-regulated in the lymph nodes in pregnant ewes, and the PGR isoform (60 kDa) and the PIBF variant (75 kDa) were expressed constantly in the lymph nodes. However, there was no expression of the PGR isoform (40 kDa) and the PIBF variant (48 kDa) at day 16 of the estrous cycle. The immunohistochemistry results confirmed that the PGR and PIBF proteins were limited to the subcapsular sinus and trabeculae in the cortex, medullary sinuses, and were localized in the cytoplasm of the specific cells. This paper reports for the first time that early pregnancy exerts its effect on the specific cells in the lymph nodes through P4, which results in the up-regulated expression of the PGR mRNA and 40 kDa isoform, the PIBF mRNA and 48 kDa variant, and is involved in the immunoregulation of the lymph nodes through a cytosolic pathway in ewes. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. 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.

    2013-01-01

    Purpose 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. Patients and Methods 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. Results 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. Conclusion 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

  15. The estrogen receptor/progesterone receptor testing errors in Newfoundland and Labrador: a journey of hope, health, and healing.

    Science.gov (United States)

    Chubbs, Katherine

    2013-01-01

    In Newfoundland and Labrador, the estrogen receptor/progesterone receptor testing errors left an unparalleled effect. Patients, families, members of healthcare teams, and many others were left shaken and wondering how the province could move forward. This article reflects on some of the processes Eastern Health had to go through to learn and grow from the experience, as well as discusses how the organization met the requirements set forth in the Commission of Inquiry report.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Membrane-bound progesterone receptors coupled to G proteins in the fungus Rhizopus nigricans.

    Science.gov (United States)

    Lenasi, Helena; Bavec, Aljosa; Zorko, Matjaz

    2002-07-16

    Steroid binding sites with high affinity for progesterone (Kd=40+/-14 nM determined by binding, and Kd=71+/-22 nM determined by displacement studies) and lower affinity for 21-hydroxyprogesterone and for testosterone, but no affinity for estradiol-17beta, onapristone and alpha-naphthoflavone were detected in the enriched plasma membrane fraction of the fungus Rhizopus nigricans. The amount of steroid binding sites is in accordance with the value of B(max)=744+/-151 fmol (mg protein)(-1). In the membrane fraction, progesterone induced about 30% activation of G proteins over basal level, as determined by GTPase activity (EC50=32+/-8 nM) and by the guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) binding rate (EC50=61+/-21 nM). The affinity of receptors for progesterone was substantially decreased in the presence of GTPgammaS and of cholera toxin. Our results suggest the existence of progesterone receptors in the membrane of Rhizopus nigricans and their coupling to G proteins.

  18. Oxidative stress effect on progesterone-induced blocking factor (PIBF) binding to PIBF-receptor in lymphocytes.

    Science.gov (United States)

    de la Haba, Carlos; Palacio, José R; Palkovics, Tamas; Szekeres-Barthó, Júlia; Morros, Antoni; Martínez, Paz

    2014-01-01

    Receptor-ligand binding is an essential interaction for biological function. Oxidative stress can modify receptors and/or membrane lipid dynamics, thus altering cell physiological functions. The aim of this study is to analyze how oxidative stress may alter receptor-ligand binding and lipid domain distribution in the case of progesterone-induced blocking factor/progesterone-induced blocking factor-receptor. For membrane fluidity regionalization analysis of MEC-1 lymphocytes, two-photon microscopy was used in individual living cells. Lymphocytes were also double stained with AlexaFluor647/progesterone-induced blocking factor and Laurdan to evaluate -induced blocking factor/progesterone-induced blocking factor-receptor distribution in the different membrane domains, under oxidative stress. A new procedure has been developed which quantitatively analyzes the regionalization of a membrane receptor among the lipid domains of different fluidity in the plasma membrane. We have been able to establish a new tool which detects and evaluates lipid raft clustering from two-photon microscopy images of individual living cells. We show that binding of progesterone-induced blocking factor to progesterone-induced blocking factor-receptor causes a rigidification of plasma membrane which is related to an increase of lipid raft clustering. However, this clustering is inhibited under oxidative stress conditions. In conclusion, oxidative stress decreases membrane fluidity, impairs receptor-ligand binding and reduces lipid raft clustering. © 2013.

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

    DEFF Research Database (Denmark)

    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...

  20. Cloning and initial characterization of nuclear and four membrane progesterone receptors in the fathead minnow(Pimephales promelas)

    Science.gov (United States)

    Both native progestagens and synthetic progestins have important effects on reproduction that are mediated through progesterone receptors (PRs). Progestagens regulate gamete maturation in vertebrates, are critical regulators of placental mammal pregnancy, and act as reproductive ...

  1. Biochemical and immunohistochemical estrogen and progesterone receptors in adenomatous hyperplasia and endometrial carcinoma: correlations with stage and other clinicopathologic features

    DEFF Research Database (Denmark)

    Nyholm, H C; Nielsen, A L; Lyndrup, J

    1992-01-01

    and immunohistochemical analysis were used. The immunohistochemical analysis receptor content was estimated semiquantitatively by a total and a cancer immunohistochemical histologic score. Multiple regression analysis was used in testing independence of established correlations. RESULTS: Estrogen and progesterone...

  2. 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...

  3. A germline TaqI restriction fragment length polymorphism in the progesterone receptor gene in ovarian carcinoma.

    OpenAIRE

    McKenna, N. J.; Kieback, D. G.; Carney, D N; Fanning, M.; McLinden, J.; Headon, D R

    1995-01-01

    Clinical outcome in ovarian carcinoma is predicted by progesterone receptor status, indicating an endocrine aspect to this disease. Peripheral leucocyte genomic DNAs were obtained from 41 patients with primary ovarian carcinoma and 83 controls from Ireland, as well as from 26 primary ovarian carcinoma patients and 101 controls in Germany. Southern analysis using a human progesterone receptor (hPR) cDNA probe identified a germline TaqI restriction fragment length polymorphism (RFLP) defined by...

  4. Characterization and ligand identification of a membrane progesterone receptor in fungi: existence of a novel PAQR in Sporothrix schenckii.

    Science.gov (United States)

    Gonzalez-Velazquez, Waleska; Gonzalez-Mendez, Ricardo; Rodriguez-del Valle, Nuri

    2012-09-07

    Adaptive responses in fungi result from the interaction of membrane receptors and extracellular ligands. Many different classes of receptors have been described in eukaryotic cells. Recently a new family of receptors classified as belonging to the progesterone-adiponectin receptor (PAQR) family has been identified. These receptors have the seven transmembrane domains characteristic of G-protein coupled receptors, but their activity has not been associated directly to G proteins. They share sequence similarity to the eubacterial hemolysin III proteins. A new receptor, SsPAQR1 (Sporothrix schenckii progesterone-adiponectinQ receptor1), was identified as interacting with Sporothrix schenckii G protein alpha subunit SSG-2 in a yeast two-hybrid assay. The receptor was identified as a member of the PAQR family. The cDNA sequence revealed a predicted ORF of 1542 bp encoding a 514 amino acids protein with a calculated molecular weight of 57.8 kDa. Protein domain analysis of SsPAQR1 showed the 7 transmembrane domains (TM) characteristic of G protein coupled receptors and the presence of the distinctive motifs that characterize PAQRs. A yeast-based assay specific for PAQRs identified progesterone as the agonist. S. schenckii yeast cells exposed to progesterone (0.50 mM) showed an increase in intracellular levels of 3', 5' cyclic adenosine monophosphate (cAMP) within the first min of incubation with the hormone. Different progesterone concentrations were tested for their effect on the growth of the fungus. Cultures incubated at 35°C did not grow at concentrations of progesterone of 0.05 mM or higher. Cultures incubated at 25°C grew at all concentrations tested (0.01 mM-0.50 mM) with growth decreasing gradually with the increase in progesterone concentration. This work describes a receptor associated with a G protein alpha subunit in S. schenckii belonging to the PAQR family. Progesterone was identified as the ligand. Exposure to progesterone increased the levels of cAMP in

  5. GABAA-receptor plasticity during long-term exposure to and withdrawal from progesterone.

    Science.gov (United States)

    Biggio, G; Follesa, P; Sanna, E; Purdy, R H; Concas, A

    2001-01-01

    The subunit composition of native gamma-aminobutyric acid type A (GABAA) receptors is an important determinant of the role of these receptors in the physiological and pharmacological modulation of neuronal excitability and associated behavior. GABAA receptors containing the alpha 1 subunit mediate the sedative-hypnotic effects of benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000), whereas the anxiolytic effects of these drugs are mediated by receptors that contain the alpha 2 subunit (Löw et al., 2000). In contrast, GABAA receptors containing the alpha 4 or alpha 6 subunits are insensitive to benzodiazepines (Barnard et al., 1998). Characterization of the functions of GABAA-receptors thus requires an understanding of the mechanisms by which the receptor subunit composition is regulated. The expression of specific GABAA-receptor subunit genes in neurons is affected by endogenous and pharmacological modulators of receptor function. The expression of GABAA-receptor subunit genes is thus regulated by neuroactive steroids both in vitro and in vivo. Such regulation occurs both during physiological conditions, such as pregnancy, and during pharmacologically induced conditions, such as pseudo-pregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Here, we summarize results obtained by our laboratory and by other groups pertaining to the effects of long-term exposure to, and subsequent withdrawal from, progesterone and its metabolite 3 alpha,5 alpha-tetrahydroprogesterone on both the expression of GABAA-receptor subunits and GABAA-receptor function.

  6. Immunologic analysis of human breast cancer progesterone receptors. 1. Immunonaffinity purification of transformed receptors and production of monoclonal antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Estes, P.A.; Suba, E.J.; Lawler-Heavner, J.; Elashry-Stowers, D.; Wei, L.L.; Toft, D.O.; Sullivan, W.P.; Horwitz, K.B.; Edwards, D.P.

    1987-09-22

    A monoclonal antibody (MAb), designated PR-6, produced against chick oviduct progesterone receptors cross-reacts with the M/sub r/ 120,000 human B receptors. An immunomatrix prepared with PR-6 was used to purify progesterone receptors (PR) from T47D human breast cancer cells. Single-step immunoaffinity chromatography results in enrichment of B receptors (identified by immunoblot with PR-6 and by photoaffinity labeling with (/sup 3/H)promegestone) to a specific activity of 1915 pmol/mg of protein (or 23% purity) and with 27% yield. Purity and yields as judged by gel electrophoresis and densitometric scanning of the B protein were approximately 1.7-fold higher due to partial loss in hormone binding activity at the elution step. B receptors purified under these conditions are transformed and biologically active. They were maintained as undergraded 120-kDa doublets and retained both hormone and DNA binding activities. These purified B receptors were used as immunogen for production of four monoclonal antibodies against human PR. Three of the MAbs, designated as B-30 (IgG/sub 1/), B-64 (IgG/sub 1/), and B-11 (IgM), are specific for B receptors. The fourth MAb, A/B-52 (IgG/sub 1/), reacts with both A and B receptors. The IgG MAbs are monospecific for human PR since they recognize and absorb native receptor-hormone complexes, displace the sedimentation of 4S receptors on salt containing sucrose gradients, and, by immunoblot assay of crude T47D cytosol, react only with receptor polypeptides. Although mice were injected with B receptors only, production of A/B-52 which recognized both A and B receptors provides evidence that these two proteins share regions of structural homology.

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

    Science.gov (United States)

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

    2016-06-01

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

  8. Progesterone receptor membrane component 1 and its role in ovarian follicle growth

    Directory of Open Access Journals (Sweden)

    John J Peluso

    2013-06-01

    Full Text Available Progesterone (P4 is synthesized in the ovary and acts directly on granulosa cells of developing ovarian follicles to suppress their rate of mitosis and apoptosis. Granulosa cells do not express nuclear progesterone receptor (PGR but rather progesterone receptor membrane component-1 (PGRMC1. PGRMC1 binds P4 and mediates P4’s actions, as evidenced by PGRMC1 siRNA studies. PGRMC1 acts by binding plasminogen activator inhibitor 1 RNA binding protein and regulating gene expression. Specifically, PGRMC1 suppresses some genes that promote cell death (i.e. Bad, Caspase-3, Caspase-4. P4 regulates gene expression in part by inhibiting PGRMC1 binding to Tcf/Lef transcription sites, thereby reducing Tcf/Lef transcriptional activity. Since Tcf/Lef transcription sites are located within the promoters of genes that initiate mitosis and/or apoptosis (i.e. c-jun and c-myc, P4-PGRMC1 mediated suppression of these Tcf/Lef regulated genes could account for P4’s actions. PGRMC1 expression is also altered in women with polycystic ovarian syndrome, premature ovarian failure and infertility. Collectively, these observations support a role for PGRMC1 in regulating human ovarian follicle development.

  9. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

    Directory of Open Access Journals (Sweden)

    Yue Yu

    Full Text Available Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1 and interlukin-6 (IL-6 by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  10. Cloning, mapping and molecular characterization of porcine progesterone receptor membrane component 2 (PGRMC2 gene

    Directory of Open Access Journals (Sweden)

    Congying Chen

    2010-01-01

    Full Text Available Progesterone plays an important role in sow reproduction by stimulating classic genomic pathways via nuclear receptors and non-genomic pathways via membrane receptors such a progesterone receptor membrane component 2 (PGRMC2. In this work, we used radiation hybrid mapping to assign PGRMC2 to pig chromosome 8 and observed that this receptor has two transcripts in pigs. The full-length cDNA of the large transcript is 1858 bp long and contains a 669-bp open reading frame (ORF encoding a protein of 223 amino acids. The shorter transcript encodes a protein of 170 amino acids. The porcine PGRMC2 gene consists of three exons 446 bp, 156 bp and 1259 bp in length. The promoter sequence is GC-rich and lacks a typical TATA box. Several putative cis-regulatory DNA motifs were identified in the 208-bp upstream genomic region. Five single nucleotide polymorphisms (SNPs were detected in introns* and the 3' UTR. RT-PCR indicated that the PGRMC2 gene is expressed ubiquitously in all pig tissues examined.

  11. Immunologic analysis of human breast cancer progesterone receptors. 2. Structure, phosphorylation, and processing

    Energy Technology Data Exchange (ETDEWEB)

    Wei, L.L.; Sheridan, P.L.; Krett, N.L.; Francis, M.D.; Toft, D.O.; Edwards, D.P.; Horwitz, K.B.

    1987-09-22

    The authors have used a monoclonal antibody (MAb) directed against chick oviduct progesterone receptors (PR), that cross-reacts with human PR, to analyze PR structure and phosphorylation. This MAb, designated PR-6, interacts only with B receptors (M/sub r/ 120,000) of T47D human breast cancer cells; it has no affinity for A receptors (M/sub r/ 94,000) or for proteolytic fragments from either protein. The antibody immunoprecipitates native B receptors and was used to study the structure of native untransformed 8S and transformed 4S receptors, using sucrose density gradient analysis, photoaffinity labeling, and gel electrophoresis. The independence of A- and B-receptor complexes was confirmed by the fining that purified, transformed B receptors bind well to DNA-cellulose. Additional studies focused on the covalent modifications of receptors. The previously described shifts in apparent molecular weight of nuclear PR following R5020 treatment using in situ photoaffinity labeling. To show whether these shifts can be explained by receptor phosphorylation, untreated cells and hormone-treated cells were metabolically labeled with (/sup 32/P)orthophosphate, and the B receptors were isolated by immunoprecipitation with PR-6 and analyzed by sodium dodecyl sulfate (SDS) gel electrophoresis. In both treatment states, B receptors were labeled in vivo with /sup 32/P, thus demonstrating directly that human PR are phosphoproteins. Since B receptors were labeled in the absence of hormone and also after their in vivo transformation by hormone, they appear to be substrates for two phosphorylation reactions, one in the untransformed state and another after they are tightly bound to chromatin. The second phosphorylation may account for the mobility shift of the receptors on SDS gels. On the basis of these data a model of human PR structure and subcellular receptor dynamics is presented.

  12. The role of estrogen and progesterone receptors in response rate to megestrol acetate: conservative treatment of stage Ia endometrial adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Yarandi F

    2010-12-01

    Full Text Available "nBackground: Surgery is the most effective treatment of well-differentiated endometrial cancer. But using systemic progestins, have been evaluated to treat the young patients with well-differentiated endometrial cancer who wish to preserve their fertility. The aim of this study was the evaluation of megestrol acetate on endometrial adenocarcino-ma with regard to the receptors."n "nMethods: This was a quasi-experimental study. In 16 infertile patients with stage Ia well-differentiated endometrial adenocarcinoma. The treatment initiated with 160mg/d of megestrol acetate and continued with 320mg/d for non-responsive cases. All of the patients followed with FD&C and hysteroscopy. The responsive patients were referred to IVF group and they were followed for three years."n "nResults: Of nine patient in the first step of the study, 4 (25% became pregnant. Eight patients underwent Total Abdominal Hysterectomy (TAH, and one was retreated conservatively. Of seven patient of second step of the study, five are under treatment at the time of closing the paper (three cases candidate for IVF and two are under 320 mg/d megestrol acetate, one patient is a candidate for hysterectomy, and one exited of study because of male infertility. All of the patients were progesterone receptor positive, and only one was estrogen receptor negative."n "nConclusion: Conservative treatment of early stage well-differentiated endometrial adenocarcinoma with progestins may be used in highly selected young patients who have not completed their family. Close long- term follow up in this special group of patients is necessary. The evaluation of estrogen and progesterone receptors assay may be useful in predicting response to the treatment.

  13. Cooperative activation of cyclin D1 and progesterone receptor gene expression by the SRC-3 coactivator and SMRT corepressor.

    Science.gov (United States)

    Karmakar, Sudipan; Gao, Tong; Pace, Margaret C; Oesterreich, Steffi; Smith, Carolyn L

    2010-06-01

    Although the ability of coactivators to enhance the expression of estrogen receptor-alpha (ERalpha) target genes is well established, the role of corepressors in regulating 17beta-estradiol (E2)-induced gene expression is poorly understood. Previous studies revealed that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full ERalpha transcriptional activity in MCF-7 breast cancer cells, and we report herein the E2-dependent recruitment of SMRT to the regulatory regions of the progesterone receptor (PR) and cyclin D1 genes. Individual depletion of SMRT or steroid receptor coactivator (SRC)-3 modestly decreased E2-induced PR and cyclin D1 expression; however, simultaneous depletion revealed a cooperative effect of this coactivator and corepressor on the expression of these genes. SMRT and SRC-3 bind directly in an ERalpha-independent manner, and this interaction promotes E2-dependent SRC-3 binding to ERalpha measured by co-IP and SRC-3 recruitment to the cyclin D1 gene as measured by chromatin IP assays. Moreover, SMRT stimulates the intrinsic transcriptional activity of all of the SRC family (p160) coactivators. Our data link the SMRT corepressor directly with SRC family coactivators in positive regulation of ERalpha-dependent gene expression and, taken with the positive correlation found for SMRT and SRC-3 in human breast tumors, suggest that SMRT can promote ERalpha- and SRC-3-dependent gene expression in breast cancer.

  14. Dietary acrylamide intake and estrogen and progesterone receptor-defined postmenopausal breast cancer risk

    DEFF Research Database (Denmark)

    Pedersen, Grete S; Hogervorst, Janneke G F; Schouten, Leo J

    2010-01-01

    Acrylamide, a potential human carcinogen, has been discovered in a variety of heat-treated carbohydrate-rich food products. Previously, dietary acrylamide intake was shown to be associated with endocrine-related cancers in humans. We assessed the association between dietary acrylamide intake...... breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status...... ratios were 1.31 (95% CI: 0.87-1.97, P (trend) = 0.26) for ER+, 1.47 (0.86-2.51, P (trend) = 0.14) for PR+, and 1.43 (0.83-2.46, P (trend) = 0.16) for ER+PR+, when comparing women in the highest quintile of acrylamide intake (median 36.8 microg/day) to women in the lowest (median 9.5 microg...

  15. Regulation of calcitonin gene-related peptide receptors in the rat uterus during pregnancy and labor and by progesterone.

    Science.gov (United States)

    Yallampalli, C; Gangula, P R; Kondapaka, S; Fang, L; Wimalawansa, S

    1999-10-01

    Calcitonin gene-related peptide (CGRP) is a potent smooth muscle relaxant in a variety of tissues. We recently demonstrated that CGRP relaxes uterine tissue during pregnancy but not during labor. In the present study we examined whether uterine (125)I-CGRP binding and immunoreactive CGRP receptors are regulated by pregnancy and labor and by sex steroid hormones. We found that (125)I-CGRP binding to membrane preparations from uteri was elevated during pregnancy and decreased during labor and postpartum. Changes in immunoreactive CGRP receptors were similar to the changes in (125)I-CGRP binding in these tissues, suggesting pregnancy-dependent regulation of CGRP receptor protein. CGRP receptors were elevated by Day 7 of gestation, and a precipitous decrease in these receptors occurred on Day 22 of gestation prior to the onset of labor. Both (125)I-CGRP-binding and immunofluorescence studies indicated that CGRP receptors were localized to myometrial cells. Hormonal control of uterine CGRP receptors was assessed by the use of antiprogesterone RU-486, progesterone, and estradiol-17beta. RU-486 induced a decrease in uterine CGRP receptors during pregnancy (Day 19). On the other hand, progesterone prevented the fall in uterine CGRP receptors at term (Day 22). In addition, progesterone also increased uterine CGRP receptors in nonpregnant, ovariectomized rats, while estradiol had no effects. These hormone-induced changes in uterine CGRP receptors were demonstrated by (125)I-CGRP-binding, Western immunoblotting, and immunolocalization methods. These results indicate that CGRP receptors and CGRP binding in the rat uterus are increased with pregnancy and decreased at term. These receptors are localized to the myometrial cells, and progesterone is required for maintaining CGRP receptors in the rat uterus. Thus, the inhibitory effects of CGRP on uterine contractility are mediated through the changes in CGRP receptors and may play a role in uterine quiescence during pregnancy.

  16. miR-129-2 mediates down-regulation of progesterone receptor in response to progesterone in breast cancer cells

    Science.gov (United States)

    Godbole, Mukul; Chandrani, Pratik; Gardi, Nilesh; Dhamne, Hemant; Patel, Kuldeep; Yadav, Neelima; Gupta, Sudeep; Badwe, Rajendra

    2017-01-01

    ABSTRACT Objective: Hormonal therapy is an important component of first line of treatment for breast cancer. Response to hormonal therapy is influenced by the progesterone receptor (PR)-status of breast cancer patients. However as an early effect, exposure to progesterone decreases expression of PR in breast cancer cells. An understanding of the mechanism underlying down-regulation of PR could help improve response to hormonal therapy. Methods: We performed small RNA sequencing of breast cancer cells for identification of microRNAs targeting PR in response to progesterone treatment. Biochemical approaches were used to validate the findings in breast cancer cells. Results: Analysis of small RNA sequencing of four breast cancer cell lines treated with progesterone revealed an up-regulation of miR-129-2 independent of the PR status of the cells. We show that miR-129-2 targets 3′UTR of PR to down-regulate its expression. Furthermore, inhibition of miR-129-2 expression rescues the down-regulation of PR in breast cancer cells. Also, the expression levels of miR-129-2 was observed to be elevated in patients with low expression of PR in the TCGA cohort (n = 359). Conclusion: miR-129-2 mediates down-regulation of PR in breast cancer cells in response to progesterone, while anti-miR-129-2 could potentiate PR expression levels among patients with inadequate PR levels. Thus, modulation of activity of miR-129-2 could stabilize PR expression and potentially improve response to hormonal therapy under adjuvant or neo-adjuvant settings. PMID:28876975

  17. Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus.

    Science.gov (United States)

    Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C; Jang, Eunjung; Lydon, John P; Korach, Kenneth S; Chung, Sang-Hyuk

    2016-04-05

    While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock-in mouse models expressing ERα mutants, we determined that the DNA-binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

  18. The effects of progesterone on the alpha2-adrenergic receptor subtypes in late-pregnant uterine contractions in vitro.

    Science.gov (United States)

    Hajagos-Tóth, Judit; Bóta, Judit; Ducza, Eszter; Samavati, Reza; Borsodi, Anna; Benyhe, Sándor; Gáspár, Róbert

    2016-06-14

    The adrenergic system and progesterone play major roles in the control of the uterine function. Our aims were to clarify the changes in function and expression of the α2-adrenergic receptor (AR) subtypes after progesterone pretreatment in late pregnancy. Sprague Dawley rats from pregnancy day 15 were treated with progesterone for 7 days. The myometrial expressions of the α2-AR subtypes were determined by RT-PCR and Western blot analysis. In vitro contractions were stimulated with (-)-noradrenaline, and its effect was modified with the selective antagonists BRL 44408 (α2A), ARC 239 (α2B/C) and spiroxatrine (α2A). The accumulation of myometrial cAMP was also measured. The activated G-protein level was investigated via GTPγS binding assays. Progesterone pretreatment decreased the contractile effect of (-)-noradrenaline through the α2-ARs. The most significant reduction was found through the α2B-ARs. The mRNA of all of the α2-AR subtypes was increased. Progesterone pretreatment increased the myometrial cAMP level in the presence of BRL 44408 (p < 0.001), spiroxatrine (p < 0.001) or the spiroxatrine + BRL 44408 combination (p < 0.05). Progesterone pretreatment increased the G-protein-activating effect of (-)-noradrenaline in the presence of the spiroxatrine + BRL 44408 combination. The expression of the α2-AR subtypes is progesterone-sensitive. It decreases the contractile response of (-)-noradrenaline through the α2B-AR subtype, blocks the function of α2A-AR subtype and alters the G protein coupling of these receptors, promoting a Gs-dependent pathway. A combination of α2C-AR agonists and α2B-AR antagonists with progesterone could be considered for the treatment or prevention of preterm birth.

  19. Uterine epithelial morphology and progesterone receptors in a mifepristone-treated viviparous lizard Pseudemoia entrecasteauxii (Squamata: Scincidae) during gestation.

    Science.gov (United States)

    Biazik, Joanna M; Parker, Scott L; Murphy, Christopher R; Thompson, Michael B

    2012-03-01

    Structural and functional changes to the uterus associated with maintenance of pregnancy are controlled primarily by steroid hormones such as progesterone. We tested the hypothesis that progesterone regulates uterine structural changes during pregnancy in the viviparous skink, Pseudemoia entrecasteauxii, by treating pregnant females with the progesterone receptor antagonist mifepristone at different stages of pregnancy. Expression and distribution of progesterone receptor was determined using Western blot and immunohistochemistry. During early pregnancy, mifepristone treatment resulted in altered uterine epithelial cell surface morphology and high embryo mortality, but did not affect females at mid and late stages of pregnancy. Females treated with mifepristone in early pregnancy exhibited abnormal uterine epithelial cell morphology such as lateral blebbing and presence of wide gaps between cells indicating loss of intercellular attachment. Chorioallantoic membranes of the embryo were not affected by mifepristone treatment. Two isoforms (55 kDa and 100 kDa) of progesterone receptor were identified using immunoblots and both isoforms were localized to the nucleus of uterine epithelial cells. The 55 kDa isoform was expressed throughout pregnancy, whereas the 100 kDa isoform was expressed during mid and especially late pregnancy. In P. entrecasteauxii, mifepristone may prevent successful embryo attachment in early pregnancy through its effects on uterine epithelial cells but may have little effect on pregnancy once the maternal-embryo structural relationship is established. © 2011 WILEY PERIODICALS, INC.

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

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    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

  1. Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer.

    Science.gov (United States)

    Leehy, Katherine A; Regan Anderson, Tarah M; Daniel, Andrea R; Lange, Carol A; Ostrander, Julie H

    2016-04-01

    Steroid hormone receptors (SRs) are heavily posttranslationally modified by the reversible addition of a variety of molecular moieties, including phosphorylation, acetylation, methylation, SUMOylation, and ubiquitination. These rapid and dynamic modifications may be combinatorial and interact (i.e. may be sequential, complement, or oppose each other), creating a vast array of uniquely modified receptor subspecies that allow for diverse receptor behaviors that enable highly sensitive and context-dependent hormone action. For example, in response to hormone or growth factor membrane-initiated signaling events, posttranslational modifications (PTMs) to SRs alter protein-protein interactions that govern the complex process of promoter or gene-set selection coupled to transcriptional repression or activation. Unique phosphorylation events allow SRs to associate or disassociate with specific cofactors that may include pioneer factors and other tethering partners, which specify the resulting transcriptome and ultimately change cell fate. The impact of PTMs on SR action is particularly profound in the context of breast tumorigenesis, in which frequent alterations in growth factor-initiated signaling pathways occur early and act as drivers of breast cancer progression toward endocrine resistance. In this article, with primary focus on breast cancer relevance, we review the mechanisms by which PTMs, including reversible phosphorylation events, regulate the closely related SRs, glucocorticoid receptor and progesterone receptor, allowing for precise biological responses to ever-changing hormonal stimuli. © 2016 Society for Endocrinology.

  2. Low Expression of Estrogen Receptor-α and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression.

    Science.gov (United States)

    Rahbar, Afsar; Touma, Joel; Costa, Helena; Davoudi, Belghis; Bukholm, Ida Rashid; Sauer, Torill; Vetvik, Katja; Geisler, Jürgen; Söderberg-Naucler, Cecilia

    2017-11-01

    The underlying mechanisms for breast cancer (BC) are largely unknown. We investigated possible correlations between the expression levels of human cytomegalovirus (HCMV) proteins and established histopathological markers of BC, including expression of estrogen receptor (ER)-α, the progesterone receptor (PgR), and HER2. We retrospectively examined paraffin-embedded biopsy specimens of BC (n = 62), ductal carcinoma in situ (n = 19), and adjacent normal breast tissue (n = 42) for HCMV immediate-early protein (IE), HCMV late antigen, HCMV DNA and RNA, and investigated possible correlations between them and expression of ER-α, PgR, and HER2. HCMV DNA and RNA were detected in all examined infiltrating BCs. High-grade positivity for HCMV-IE was detected in 77% of infiltrating BCs, 39% of ductal carcinomas in situ, and 7% of tumor-free breast tissue samples. HCMV expression correlated inversely with ER-α (P = .02) and PgR (P = .003) expression. HER2 expression was also reduced in HCMV-positive samples without reaching a level of statistical significance (P = .09). The negative correlation between high-grade expression HCMV-IE and hormone receptor expression suggests a role for HCMV in hormone receptor-negative BC tumors, possibly by forcing BC cells into a more aggressive phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Progesterone receptor gene (PROGINS) polymorphism correlates with late onset of migraine.

    Science.gov (United States)

    Palmirotta, Raffaele; Barbanti, Piero; Ialongo, Cristiano; De Marchis, Maria Laura; Alessandroni, Jhessica; Egeo, Gabriella; Aurilia, Cinzia; Fofi, Luisa; Valente, Maria Giovanna; Ferroni, Patrizia; Della-Morte, David; Guadagni, Fiorella

    2015-03-01

    Progesterone influences central neuronal excitability, a key event in migraine pathophysiology. Progesterone receptor gene (PGR) rs1042838 (G/T - Val660Leu) variant is indicative of PROGINS haplotype and associated to a reduced PGR activity. With the aim of investigating whether any type of association existed between this genetic variant and migraine pathophysiology, genotyping was performed in 380 consecutive migraine patients and 185 age-, sex-, and race-ethnicity-matched healthy controls from Interinstitutional Multidisciplinary BioBank (BioBIM) of IRCCS San Raffaele Pisana, Rome, Italy. rs1042838 genotypes did not correlate with demographics or clinical migraine features. However, TT (Leu) genotype was significantly associated with a later age of migraine onset: Patients affected by migraine with aura showed a linear relationship between copy number of the T allele carried by the individual and the age of migraine onset. Our data suggest that the PROGINS PGR polymorphism does not directly predispose to migraine but significantly delays migraine onset probably via a reduction in brain neuronal excitability.

  4. Efficient Prediction of Progesterone Receptor Interactome Using a Support Vector Machine Model

    Directory of Open Access Journals (Sweden)

    Ji-Long Liu

    2015-03-01

    Full Text Available Protein-protein interaction (PPI is essential for almost all cellular processes and identification of PPI is a crucial task for biomedical researchers. So far, most computational studies of PPI are intended for pair-wise prediction. Theoretically, predicting protein partners for a single protein is likely a simpler problem. Given enough data for a particular protein, the results can be more accurate than general PPI predictors. In the present study, we assessed the potential of using the support vector machine (SVM model with selected features centered on a particular protein for PPI prediction. As a proof-of-concept study, we applied this method to identify the interactome of progesterone receptor (PR, a protein which is essential for coordinating female reproduction in mammals by mediating the actions of ovarian progesterone. We achieved an accuracy of 91.9%, sensitivity of 92.8% and specificity of 91.2%. Our method is generally applicable to any other proteins and therefore may be of help in guiding biomedical experiments.

  5. Neural Analyses Validate and Emphasize the Role of Progesterone Receptor in Breast Cancer Progression and Prognosis.

    Science.gov (United States)

    Caronongan, Arturo; Venturini, Barbara; Canuti, Debora; Dlay, Satnam; Naguib, Raouf N G; Sherbet, Gajanan V

    2016-04-01

    Oestrogen receptor (ER) expression is routinely measured in breast cancer management, but the clinical merits of measuring progesterone receptor (PR) expression have remained controversial. Hence the major objective of this study was to assess the potential of PR as a predictor of response to endocrine therapy. We report on analyses of the relative importance of ER and PR for predicting prognosis using robust multilayer perceptron artificial neural networks. Receptor determinations use immunohistochemical (IHC) methods or radioactive ligand binding assays (LBA). In view of the heterogeneity of intratumoral receptor distribution, we examined the relative merits of the IHC and LBA methods. Our analyses reveal a more significant correlation of IHC-determined PR than ER with both nodal status and 5-year disease-free survival (DFS). In LBA, PR displayed higher correlation with survival and ER with nodal status. There was concordance of correlation of PR with DFS by both IHC and LBA. This study suggests a clear distinction between PR and ER, with PR displaying greater correlation than ER with disease progression and prognosis, and emphasizes the marked superiority of the IHC method over LBA. These findings may be valuable in the management of patients with breast cancer. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  6. Immunohistochemical expression of estrogens and progesterone receptors in carcinoma ex pleomorphic adenoma-undifferentiated and adenocarcinoma types.

    Science.gov (United States)

    Tarakji, Bassel; Nassani, Mohammad Z; Sloan, Philip

    2010-05-01

    Cancer of the salivary gland is one of the common cancers in the head and the neck regions. This type of cancer develops in the minor and the major salivary glands, and it sometimes metastasizes to other organs, particularly the lung. Morphologic mimicry and similarity in the expression of steroid hormone receptors between salivary gland tumours and breast tumours are well-known phenomena and are occasionally debated in the field of surgical pathology. The expression of sex hormone receptors in some tumours suggests a role for these receptors in tumor pathogenesis and therapy. Previous studies of the expression of estrogens and progesterone receptors in salivary gland tumours have reported conflicting results. Our study aimed to characterize alteration in the immunohistochemical expression of oestrogens receptor and progesterone receptor in the tumour cells of carcinoma arising in pleomorphic adenoma. 27 cases of carcinoma arising in pleomorphic adenoma (undifferentiated and adenocarcinoma types) were examined. The results showed that 27 (100 %) of 27 cases had negative nuclear staining for either oestrogens or progesterone receptors. Our data suggest that carcinomas arising in pleomorphic adenoma were not dependent on endocrine function.

  7. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.

    Science.gov (United States)

    Friel, Anne M; Zhang, Ling; Pru, Cindy A; Clark, Nicole C; McCallum, Melissa L; Blok, Leen J; Shioda, Toshi; Peluso, John J; Rueda, Bo R; Pru, James K

    2015-01-28

    Endometrial cancer is the leading gynecologic cancer in women in the United States with 52,630 women predicted to be diagnosed with the disease in 2014. The objective of this study was to determine if progesterone (P4) receptor membrane component 1 (PGRMC1) influenced endometrial cancer cell viability in response to chemotherapy in vitro and in vivo. A lentiviral-based shRNA knockdown approach was used to generate stable PGRMC1-intact and PGRMC1-deplete Ishikawa endometrial cancer cell lines that also lacked expression of the classical progesterone receptor (PGR). Progesterone treatment inhibited mitosis of PGRMC1-intact, but not PGRMC1-deplete cells, suggesting that PGRMC1 mediates the anti-mitotic actions of P4. To test the hypothesis that PGRMC1 attenuates chemotherapy-induced apoptosis, PGRMC1-intact and PGRMC1-deplete cells were treated in vitro with vehicle, P4 (1 µM), doxorubicin (Dox, 2 µg/ml), or P4 + Dox for 48 h. Doxorubicin treatment of PGRMC1-intact cells resulted in a significant increase in cell death; however, co-treatment with P4 significantly attenuated Dox-induced cell death. This response to P4 was lost in PGRMC1-deplete cells. To extend these observations in vivo, a xenograft model was employed where PGRMC1-intact and PGRMC1-deplete endometrial tumors were generated following subcutaneous and intraperitoneal inoculation of immunocompromised NOD/SCID and nude mice, respectively. Tumors derived from PGRMC1-deplete cells grew slower than tumors from PGRMC1-intact cells. Mice harboring endometrial tumors were then given three treatments of vehicle (1:1 cremophor EL: ethanol + 0.9% saline) or chemotherapy [Paclitaxel (15 mg/kg, i.p.) followed after an interval of 30 minutes by CARBOplatin (50 mg/kg)] at five day intervals. In response to chemotherapy, tumor volume decreased approximately four-fold more in PGRMC1-deplete tumors when compared with PGRMC1-intact control tumors, suggesting that PGRMC1 promotes tumor cell viability

  8. The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 are Different Binding Sites Derived From Independent Genes

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    Uyen B. Chu

    2015-11-01

    Full Text Available The sigma-2 receptor (S2R is a potential therapeutic target for cancer and neuronal diseases. However, the identity of the S2R has remained a matter of debate. Historically, the S2R has been defined as (1 a binding site with high affinity to 1,3-di-o-tolylguanidine (DTG and haloperidol but not to the selective sigma-1 receptor ligand (+-pentazocine, and (2 a protein of 18–21 kDa, as shown by specific photolabeling with [3H]-Azido-DTG and [125I]-iodoazido-fenpropimorph ([125I]-IAF. Recently, the progesterone receptor membrane component 1 (PGRMC1, a 25 kDa protein, was reported to be the S2R (Nature Communications, 2011, 2:380. To confirm this identification, we created PGRMC1 knockout NSC34 cell lines using the CRISPR/Cas9 technology. We found that in NSC34 cells devoid of or overexpressing PGRMC1, the maximum [3H]-DTG binding to the S2R (Bmax as well as the DTG-protectable [125I]-IAF photolabeling of the S2R were similar to those of wild-type control cells. Furthermore, the affinities of DTG and haloperidol for PGRMC1 (KI = 472 μM and 350 μM, respectively, as determined in competition with [3H]-progesterone, were more than 3 orders of magnitude lower than those reported for the S2R (20–80 nM. These results clarify that PGRMC1 and the S2R are distinct binding sites expressed by different genes.

  9. Primate-specific Melanoma Antigen-A11 Regulates Isoform-specific Human Progesterone Receptor-B Transactivation*

    Science.gov (United States)

    Su, Shifeng; Blackwelder, Amanda J.; Grossman, Gail; Minges, John T.; Yuan, Lingwen; Young, Steven L.; Wilson, Elizabeth M.

    2012-01-01

    Progesterone acting through the progesterone receptor (PR) and its coregulators prepares the human endometrium for receptivity to embryo implantation and maintains pregnancy. The menstrual cycle-dependent expression of melanoma antigen-A11 (MAGE-11) in the mid-secretory human endometrium suggested a novel function in human PR signaling. Here we show that MAGE-11 is an isoform-specific coregulator responsible for the greater transcriptional activity of human PR-B relative to PR-A. PR was recruited to progesterone response regions of progesterone-regulated FK506-binding protein 5 (FKBP5) immunophilin and small Ras family G protein cell growth inhibitor RASD1 genes. Expression of MAGE-11 lentivirus shRNA in human endometrial Ishikawa cells expressing PR-B showed that MAGE-11 is required for isoform-specific PR-B up-regulation of FKBP5. In contrast, MAGE-11 was not required for progesterone up-regulation of RASD1 in endometrial cells expressing the PR-A/B heterodimer. Target gene specificity of PR-B depended on the synergistic actions of MAGE-11 and p300 mediated by the unique PR-B NH2-terminal 110LLXXVLXXLL119 motif that interacts with the MAGE-11 F-box region in a phosphorylation- and ubiquitinylation-dependent manner. A progesterone-dependent mechanism is proposed in which MAGE-11 and p300 increase PR-B up-regulation of the FKBP5 gene. MAGE-11 down-regulates PR-B, similar to the effects of progesterone, and interacts with FKBP5 to stabilize a complex with PR-B. We conclude that the coregulator function of MAGE-11 extends to isoform-specific regulation of PR-B during the cyclic development of the human endometrium. PMID:22891251

  10. 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).

    Science.gov (United States)

    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.

  11. Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice.

    Science.gov (United States)

    Desroziers, Elodie; Brock, Olivier; Bakker, Julie

    2017-04-01

    We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre- and early postnatal estradiol defeminized the ability to show lordosis in adulthood, whereas prepubertal estradiol feminized this ability. Furthermore, we found that estradiol upregulates progesterone receptors (PR) during development, inducing both a male-and female-typical pattern of PR expression in the mouse hypothalamus. In the present study, we took advantage of a newly developed PR antagonist (ZK 137316) to determine whether PR contributes to either male- or female-typical sexual differentiation. Thus groups of male and female C57Bl/6j mice were treated with ZK 137316 or OIL as control: males were treated neonatally (P0-P10), during the critical period for male sexual differentiation, and females were treated prepubertally (P15-P25), during the critical period for female sexual differentiation. In adulthood, mice were tested for sexual behavior. In males, some minor effects of neonatal ZK treatment on sexual behavior were observed: latencies to the first mount, intromission and ejaculation were decreased in neonatally ZK treated males; however, this effect disappeared by the second mating test. By contrast, female mice treated with ZK during the prepubertal period showed significantly less lordosis than OIL-treated females. Mate preferences were not affected in either males or females treated with ZK during development. Taken together, these results suggest a role for PR and thus perhaps progesterone in the development of lordosis behavior in female mice. By contrast, no obvious role for PR can be discerned in the development of male sexual behavior. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Effect of long-term treatment with steroid hormones or tamoxifen on the progesterone receptor and androgen receptor in the endometrium of ovariectomized cynomolgus macaques

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    Cline J Mark

    2003-02-01

    Full Text Available Abstract The progesterone receptor (PR and androgen receptor (AR belong to the nuclear receptor superfamily. Two isoforms of PR (A and B have been identified with different functions. The expression of AR, each isoform of PR and their involvement in long-term effects on the endometrium after hormonal replacement therapy (HRT or tamoxifen (TAM treatment is not known. The aims of this study were to determine PR(A+B, PRB and AR distribution by immunohistochemistry in the macaque (Macaca fascicularis endometrium. Ovariectomized (OVX animals were orally treated continuously for 35 months with either conjugated equine estrogens (CEE; medroxyprogesterone acetate (MPA; the combination of CEE/MPA; or TAM. Treatment with CEE/MPA tended to down-regulate PR in the superficial glands, but increased it in the stroma. TAM treatment increased both the PR and PRB levels in the stroma. Overall, less than 20% of the cells were positive for the PRB isoform and less variation was observed after steroid treatment. AR was found in the stroma, mainly distributed in the basal layer of the endometrium in the OVX and steroid treated groups, but was absent in the TAM treated group. No AR was found in the glandular epithelium. The present data show that long-term hormone treatment affects the PR level, and also the ratio between PRA and PRB in the endometrium.

  13. 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

  14. Regulation of GnRH receptors by progesterone and inhibin in ovine pituitary cell culture

    Energy Technology Data Exchange (ETDEWEB)

    Laws, S.C.

    1988-01-01

    The effects of progesterone (P{sub 4}) and the gonadal protein, inhibin, on gonadotropin-releasing hormone (GnRH) receptor number and binding affinity were investigated in vitro, using ovine pituitary cells in culture. Changes in GnRH binding were correlated with GnRH-stimulated luteinizing hormone (LH) release following pretreatment with P{sub 4} and inhibin. Ovine pituitary cells in culture were preincubated with P{sub 4} or porcine inhibin (I{sub P}) for 24 or 48 hours (h). Cells were collected and analyzed for GnRH binding using a radioligand-receptor assay. des-Gly{sup 10}-(D-Ala{sup 6})-LHRH-ethyl-amide was used as the radiolabeled GnRh superagonist analog (mono-{sup 125}I-GnRH-A) and as competing ligand. Treatment with P{sub 4} progressively decreased GnRH-A binding capacity by 44.3% and 71.8% of the control following pretreatment for 24 or 48 h, respectively. When P{sub 4} was removed from the cultures, GnRH-A binding capacity partially returned to control levels within 24 h. Decreased GnRH-A binding was closely correlated with the reduction in GnRH-stimulated LH release which was observed following 24 or 48 h pretreatment with P{sub 4}.

  15. [Effects of ursodeoxycholic acid on the liver plasma membrane fluidity, hepatic glutathione concentration, hepatic estrogen receptors and progesterone receptors in pregnant rats with ethinylestradiol and progesterone induced intrahepatic cholestasis].

    Science.gov (United States)

    Shi, Qing-yun; Kong, Bei-hua; Ma, Kai-dong; Zhang, Xiang-li; Jiang, Sen

    2003-11-01

    To explore the effects of ursodeoxycholic acid (UDCA) on the fluidity of hepatic plasma membrane, glutathione concentration in liver, hepatic estrogen receptors and progesterone receptors in pregnant rats with ethinylestradiol and progesterone induced intrahepatic cholestasis. sixty clean SD pregnant rats were selected and divided into three groups at random. Since the 13th day of pregnancy after taking blood, normal group was injected subcutaneously with refined vegetable oil 2.5 ml x kg(-1) x d(-1). Control group and treatment group were injected subcutaneously with the solution of progesterone 75 mg x kg(-1) x d(-1) and 17-alpha-ethynylestradio 1.25 mg x kg(-1) x d(-1) till the 17th day. Since the 17th day control group, normal group were fedwish 0.9% natriichloridi solution 5 ml x kg(-1) x d(-1); Treatment group was fedwish UDCA 50 mg x kg(-1) x d(-1) every day. On the 21th day, all rats were killed. Then the livers were collected for study. Membrane fluidity was measured by fluorescence polarization using 1,6-diphenyl-1,3,5-hexatriene (DPH) as a probe. Glutathione concentration was measured by 5,5'-dithionbis (2-nitrobenzoic acid) (DTNB). Estrogen receptors and progesterone receptors were measured by flow cytometry. (1) Hepatic plasma membrane fluidity and glutathione (GSH) concentration: significantly lower level of GSH concentration and higher fluorescence polarization (P) were detected in control group (GSH: 1.13 +/- 0.03, P: 0.149 +/- 0.008) in comparison with normal group (GSH: 2.11 +/- 0.07, P: 0.132 +/- 0.004, P 0.05). Ursodeoxycholic acid may be effective drug in treatment intrahepatic cholestasis of pregnancy.

  16. Extra-nuclear signaling of progesterone receptor to breast cancer cell movement and invasion through the actin cytoskeleton.

    Directory of Open Access Journals (Sweden)

    Xiao-Dong Fu

    2008-07-01

    Full Text Available Progesterone plays a role in breast cancer development and progression but the effects on breast cancer cell movement or invasion have not been fully explored. In this study, we investigate the actions of natural progesterone and of the synthetic progestin medroxyprogesterone acetate (MPA on actin cytoskeleton remodeling and on breast cancer cell movement and invasion. In particular, we characterize the nongenomic signaling cascades implicated in these actions. T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices in the presence of both progestins. Exposure to the hormones triggers a rapid remodeling of the actin cytoskeleton and the formation of membrane ruffles required for cell movement, which are dependent on the rapid phosphorylation of the actin-regulatory protein moesin. The extra-cellular small GTPase RhoA/Rho-associated kinase (ROCK-2 cascade plays central role in progesterone- and MPA-induced moesin activation, cell migration and invasion. In the presence of progesterone, progesterone receptor A (PRA interacts with the G protein G alpha(13, while MPA drives PR to interact with tyrosine kinase c-Src and to activate phosphatidylinositol-3 kinase, leading to the activation of RhoA/ROCK-2. In conclusion, our findings manifest that progesterone and MPA promote breast cancer cell movement via rapid actin cytoskeleton remodeling, which are mediated by moesin activation. These events are triggered by RhoA/ROCK-2 cascade through partially differing pathways by the two compounds. These results provide original mechanistic explanations for the effects of progestins on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers.

  17. Progesterone-dependent immunomodulation.

    Science.gov (United States)

    Szekeres-Bartho, J; Polgar, B; Kozma, N; Miko, E; Par, G; Szereday, L; Barakonyi, A; Palkovics, T; Papp, O; Varga, P

    2005-01-01

    The biological effects of progesterone are mediated by a 34-kDa protein named the progesterone-induced blocking factor (PIBF). PIBF, synthesized by lymphocytes of healthy pregnant women in the presence of progesterone, inhibits arachidonic acid release as well as NK activity, and modifies the cytokine balance. Within the cell the full-length PIBF is associated with the centrosome, while secretion of shorter forms is induced by activation of the cell. PIBF induces nuclear translocation of STAT6 as well as PKC phosphorylation and exerts a negative effect on STAT4 phosphorylation. The concentration of PIBF in pregnancy urine is related to the positive or negative outcome of pregnancy; furthermore, premature pregnancy termination is predictable by lower than normal pregnancy PIBF values. In vivo data suggest the biological importance of the above findings. Treatment of pregnant Balb/c mice with the antiprogesterone RU 486 results in an increased resorption rate, which is associated with the inability of spleen cells to produce PIBF. High resorption rates induced by progesterone receptor block as well as those due to high NK activity are corrected by simultaneous PIBF treatment.

  18. 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.

  19. Progesterone receptor isoform analysis by quantitative real-time polymerase chain reaction in formalin-fixed, paraffin-embedded canine mammary dysplasias and tumors

    DEFF Research Database (Denmark)

    Guil-Luna, S.; Stenvang, Jan; Brünner, Nils

    2014-01-01

    Cloning and sequencing of the progesterone receptor gene in dogs have revealed 2 isoforms, A and B, transcribed from a single gene. Distribution of isoforms A and B in canine mammary lesions has hitherto been investigated only by Western blot analysis. This study analyzed progesterone receptor...... and its isoforms in formalin-fixed, paraffin-embedded tissue samples from canine mammary lesions (4 dysplasias, 10 benign tumors, and 46 carcinomas) using 1-step SYBR Green quantitative real-time polymerase chain reaction (RT-qPCR). Progesterone receptor was expressed in 75% of dysplasias, all benign...... of the canine mammary gland. These findings will facilitate future research into the role of progesterone receptor isoforms in the progression of canine mammary tumors....

  20. 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

  1. Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi.

    Science.gov (United States)

    Ziyan, Jiang; Huaibin, Ren; Xiaotian, Ma; Guangtong, She; Xiaoqing, Chen; Zijiang, Dong; Ziyue, Jiang; We, De; Lizhou, Sun

    2010-05-01

    The progesterone receptor (PR)-A/B ratio in the myometrium is reported to be closely related to labor onset. This might represent a potential target for therapeutic interventions for postterm and preterm deliveries, though the mechanisms currently remain unknown. The aim of this study was to investigate the regulation mechanism of PR-A and B expression in human preterm, term, and postterm placental villi. Experimental study. People's Hospital of Jiangsu Province, China. Singleton women of preterm (PRNIL, not in labor, n = 10), term (TNIL, not in labor, n = 10; TIL, in labor, n = 10), and postterm (PONIL, not in labor, n = 10) cesarean deliveries. The PR-A/PR-B mRNA and protein ratios were analyzed using real-time reverse transcription-polymerase chain reaction and western blots in villi from preterm, term, postterm groups. PONIL and PRNIL villi were incubated with prostaglandin F(2alpha) (PG) and indomethacin for 72 hours, respectively, and the PR-A/PR-B mRNA and protein ratios and p38 signaling pathway were explored. The PR-A/PR-B ratio was highest in TIL, followed by PRNIL, PONIL and TNIL. Indomethacin significantly up-regulated PR-B expression, thereby decreasing the PR-A/PR-B ratio (p postterm deliveries.

  2. Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood.

    Science.gov (United States)

    Willing, Jari; Wagner, Christine K

    2016-01-01

    Numerous psychiatric and behavioral disorders such as autism, attention deficit disorder and schizophrenia may involve disruptions in the development of the mesocortical dopamine pathway, consisting of dopaminergic projections from the midbrain ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC). Nuclear steroid hormone receptors are powerful transcription factors and can profoundly and permanently alter fundamental processes of neural development. Nuclear progesterone receptor (PR) is transiently expressed in both the VTA and the PFC of rodents during perinatal life, suggesting that PR may regulate the normal development of this important behavioral circuit. Here, we demonstrate that virtually all PR-immunoreactive (PR-ir) cells in the VTA also express tyrosine hydroxylase immunoreactivity (TH-ir). In addition, retrograde tract tracing reveals that many PR-ir cells in the VTA project to the mPFC. Administration of a PR antagonist to rats during the neonatal period decreased TH-ir fiber density in the prelimbic mPFC of juveniles (postnatal day 25) and decreased levels of TH-ir in the VTA of adults. Neonatal treatment with a PR antagonist impaired adult performance on a passive inhibitory avoidance task and an attentional set-shifting task, measures of behavioral inhibition/impulsivity and cognitive flexibility, respectively. TH-ir levels in the VTA were reduced and cognitive flexibility was impaired in PR knockout mice as well. These findings provide novel insights into a potential role for PR in the developmental etiology of behavioral disorders that involve impairments in complex cognitive behaviors and have implications for the use of synthetic progestins in humans during critical neurodevelopmental periods. © 2015 S. Karger AG, Basel.

  3. Bioinformatic analysis of cis-regulatory interactions between progesterone and estrogen receptors in breast cancer

    Directory of Open Access Journals (Sweden)

    Matloob Khushi

    2014-11-01

    Full Text Available Chromatin factors interact with each other in a cell and sequence-specific manner in order to regulate transcription and a wealth of publically available datasets exists describing the genomic locations of these interactions. Our recently published BiSA (Binding Sites Analyser database contains transcription factor binding locations and epigenetic modifications collected from published studies and provides tools to analyse stored and imported data. Using BiSA we investigated the overlapping cis-regulatory role of estrogen receptor alpha (ERα and progesterone receptor (PR in the T-47D breast cancer cell line. We found that ERα binding sites overlap with a subset of PR binding sites. To investigate further, we re-analysed raw data to remove any biases introduced by the use of distinct tools in the original publications. We identified 22,152 PR and 18,560 ERα binding sites (<5% false discovery rate with 4,358 overlapping regions among the two datasets. BiSA statistical analysis revealed a non-significant overall overlap correlation between the two factors, suggesting that ERα and PR are not partner factors and do not require each other for binding to occur. However, Monte Carlo simulation by Binary Interval Search (BITS, Relevant Distance, Absolute Distance, Jaccard and Projection tests by Genometricorr revealed a statistically significant spatial correlation of binding regions on chromosome between the two factors. Motif analysis revealed that the shared binding regions were enriched with binding motifs for ERα, PR and a number of other transcription and pioneer factors. Some of these factors are known to co-locate with ERα and PR binding. Therefore spatially close proximity of ERα binding sites with PR binding sites suggests that ERα and PR, in general function independently at the molecular level, but that their activities converge on a specific subset of transcriptional targets.

  4. Effect of dietary fiber intake on breast cancer risk according to estrogen and progesterone receptor status.

    Science.gov (United States)

    Zhang, C-X; Ho, S C; Cheng, S-Z; Chen, Y-M; Fu, J-H; Lin, F-Y

    2011-08-01

    There is few data on the association between dietary fiber intake and estrogen receptor (ER)/progesterone receptor (PR)-defined breast cancer risk. The present study aimed to investigate the associations between total dietary fiber and dietary fiber fractions intake and breast cancer risk by ER and PR status in a hospital-based case-control study among Chinese women. Four hundred and thirty-eight cases with primary breast cancer were consecutively recruited from June 2007 to August 2008 and frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). A validated food frequency questionnaire was used to assess the dietary intake through a face-to-face interview. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence interval (CI) after adjusting for various potential confounders. A statistically significant inverse association was found between total dietary fiber and fiber fractions intake and breast cancer risk. The adjusted ORs (95% CIs) for the highest versus the lowest quartile of intake were 0.31 (0.20-0.47) for total dietary fiber, 0.73 (0.48-1.11) for soy fiber, 0.48 (0.22-0.97) for vegetable fiber and 0.54 (0.31-0.92) for fruit fiber. No association was observed for cereal fiber intake and risk. An inverse association between dietary fiber intake and breast cancer risk was observed in ER+, ER-, PR+, ER+PR+ and ER-PR+ tumors. Our results suggest that consumption of total dietary fiber and fiber from vegetable and fruit was inversely associated with breast cancer risk. These inverse associations were more prominent in some subtypes of ER and PR breast cancers.

  5. Integration of estrogen and progesterone receptors with pathological and molecular prognostic factors in breast cancer patients.

    Science.gov (United States)

    Gago, F E; Tello, O M; Diblasi, A M; Ciocca, D R

    1998-12-01

    In this study we have examined biopsies from women with localized primary breast cancer to investigate the prognostic performance of estrogen receptors (ER) and progesterone receptors (PR) for estimating the metastatic probability of the patients, and to explore whether discrimination gets better by combining clinicopathological and other molecular parameters into a score. This prospective study involved 205 patients with a median follow-up of 5 y. Among the evaluated clinicopathological data were: patient's age; tumor size; axillary lymph node involvement; and tumor grade. The most representative tumor samples were derived to a single laboratory for immunohistochemical evaluation of the following molecular markers: ER, PR, proliferating cell nuclear antigen (PCNA), p53 protein product, erbB-2 (HER-2/neu) oncoprotein, and P170 glycoprotein (mdrl gen product). Distant metastases (study endpoint) appeared in 19.5% (40/205) of the patients, most of these patients presented a mixture of poor, regular and good prognostic factors. Disease-free survival analysis procedures (Kaplan-Meier method) identified tumor size, axillary lymph node involvement, tumor grade, receptor status, PCNA, p53, erbB-2 and P170 as useful prognostic factors. Proportional hazard regression analysis (Cox) identified in order of importance erbB-2, tumor size, receptors status, tumor grade and PCNA as useful prognostic factors. To facilitate the evaluation of the prognostic factors, a practical and simple score system was derived. A high pathological score identified 65% of the patients that developed distant metastases, while a high molecular score was obtained in 57% of patients with metastatic disease. There was a significant improvement in the diagnosis of probability of being with distant metastases when the pathological score was combined with the molecular score, 82% of the patients with distant metastases showed an elevated combined score. Validation of this scoring system will need further

  6. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.

    NARCIS (Netherlands)

    Hammond, M.E.; Hayes, D.F.; Dowsett, M.; Allred, D.C.; Hagerty, K.L.; Badve, S.; Fitzgibbons, P.L.; Francis, G.; Goldstein, N.S.; Hayes, M.; Hicks, D.G.; Lester, S.; Love, R.; Mangu, P.B.; McShane, L.; Miller, K.; Osborne, C.K.; Paik, S.; Perlmutter, J.; Rhodes, A.; Sasano, H.; Schwartz, J.N.; Sweep, F.C.; Taube, S.; Torlakovic, E.E.; Valenstein, P.; Viale, G.; Visscher, D.; Wheeler, T.; Williams, R.B.; Wittliff, J.L.; Wolff, A.C.

    2010-01-01

    PURPOSE: To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. METHODS: The American Society of Clinical Oncology and the College of

  7. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version).

    NARCIS (Netherlands)

    Hammond, M.E.; Hayes, D.F.; Dowsett, M.; Allred, D.C.; Hagerty, K.L.; Badve, S.; Fitzgibbons, P.L.; Francis, G.; Goldstein, N.S.; Hayes, M.; Hicks, D.G.; Lester, S.; Love, R.; Mangu, P.B.; McShane, L.; Miller, K.; Osborne, C.K.; Paik, S.; Perlmutter, J.; Rhodes, A.; Sasano, H.; Schwartz, J.N.; Sweep, F.C.; Taube, S.; Torlakovic, E.E.; Valenstein, P.; Viale, G.; Visscher, D.; Wheeler, T.; Williams, R.B.; Wittliff, J.L.; Wolff, A.C.

    2010-01-01

    PURPOSE: To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. METHODS: The American Society of Clinical Oncology and the College of

  8. Immunohistochemical features of progesterone receptors expression of placental barrier in women with multiple pregnancies resulting from assisted reproduction

    Directory of Open Access Journals (Sweden)

    T. D. Zadorozhna

    2016-01-01

    Full Text Available Hormonal disorders are one of the main known causes of miscarriage and preterm birth in multiple pregnancies resulting from assisted reproductive technology (ART. Progesterone and the number of its receptors play an important role in the preservation and prolongation of pregnancy and it is the pressing issue of our time. The study of placentas, as the main site of synthesis of progesterone, has high informative potential and it is the most important diagnostic object, and information received by its research is essential for the full conclusion on the causes, mechanisms, close and long-term effects of multiple pregnancy pathology. Aim. The aim of our study was to investigate immunohistochemical features of placentas from women with dichorionic diamniotic twin pregnancies in spontaneous fertilization and after use of assisted reproductive technology (ART. Methods and results. According to this goal we examined 94 women, 44 of whom had multiple pregnancies due to ART, 42 with separate multiple pregnancy and 38 women with a singleton pregnancy. We carried out clinical and statistical analysis of the course of pregnancy and childbirth in the studied groups. During the study it was found that multiple pregnancies due to assisted reproduction belong to the high risk of gestation, at which premature births occur much more frequently than in singleton pregnancies. We were the first to carry out the immunohistochemical study of placentas in which the highest expression of progesterone receptors in the nuclei of cells of decidua (45% related to the parent structure of the placenta from women with multiple pregnancies caused by ART is found. It is also found that with increasing gestational age, there has been a significant decrease in the expression of the activity of progesterone receptors (from 45 to 2.5%, regardless of the method of conception and the number of fetuses. Conclusions. The results of the study point to the definitive link of structures of

  9. Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression

    Science.gov (United States)

    Esber, Nathalie; Le Billan, Florian; Resche-Rigon, Michèle; Loosfelt, Hugues; Lombès, Marc; Chabbert-Buffet, Nathalie

    2015-01-01

    The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required. PMID:26474308

  10. Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression.

    Directory of Open Access Journals (Sweden)

    Nathalie Esber

    Full Text Available The progesterone receptor (PR with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4 and ulipristal acetate (UPA, a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.

  11. Expression and localisation of oestrogen and progesterone receptors in the bovine mammary gland during development, function and involution.

    Science.gov (United States)

    Schams, D; Kohlenberg, S; Amselgruber, W; Berisha, B; Pfaffl, M W; Sinowatz, F

    2003-05-01

    It is now well established that oestrogen and progesterone are absolutely essential for mammary gland development. Lactation can be induced in non-pregnant animals by sex steroid hormone treatment. Most of the genomic actions of oestrogens are mediated by two oestrogen receptors (ER)-alpha and ERbeta, and for gestagens in ruminants by the progesterone receptor (PR). Our aim was the evaluation of mRNA expression and protein (localisation and Western blotting) during mammogenesis, lactogenesis, galactopoiesis (early, middle and late) and involution (8, 24, 28, 96-108 h and 14-28 days after the end of milking) in the bovine mammary gland (total no. 53). During these stages, the mRNA was assessed by means of real-time RT-PCR (LightCycler). The protein for ERalpha, ERbeta and PR was localised by immunohistochemistry and Western blotting. The mRNA expression results indicated the existence of ERalpha, ERbeta and PR in bovine mammary gland. Both ERalpha and PR are expressed in fg/ micro g total RNA range. The highest mRNA expression was found for ERalpha and PR in the tIssue of non-pregnant heifers, followed by a significant decrease to a lower level at the time of lactogenesis with low concentrations remaining during lactation and the first 4 weeks of involution. In contrast, the expression of ERbeta was about 1000-fold lower (ag/ micro g total RNA) and showed no clear difference during the stages examined, with a significant increase only 2-4 weeks after the end of milking. Immunolocalisation for ERalpha revealed a strong positive staining in nuclei of lactocytes in non-pregnant heifers, became undetectable during pregnancy, lactogenesis and lactation, and was again detectable 14-28 days after the end of milking. In contrast, PR was localised in the nuclei of epithelial cells in the mammary tIssue of non-pregnant heifers, in primigravid animals, and during late lactation and involution. During lactogenesis, peak and mid lactation, fewer nuclei of epithelial cells were

  12. Maternal hypothyroidism decreases progesterone receptor expression in the cortical subplate of foetal rat brain.

    Science.gov (United States)

    Jahagirdar, V; Zoeller, T R; Tighe, D P; Wagner, C K

    2012-08-01

    Steroid hormones exert profound effects on the development of brain areas controlling complex cognitive function in adulthood. One class, progestins, may contribute by acting on the progestin receptor (PR), which is transiently expressed in a critical layer of developing cortex: the subplate. PR expression in the subplate coincides with the establishment of ongoing cortical connectivity and may play an important organisational role. Identification of the factor(s) that regulate the precise timing of PR expression within subplate may help elucidate the function of PR. Thyroid hormone may interact with hormone response elements within the PR gene. The present study examined the effects of maternal hypothyroidism on levels of PR immunoreactivity (PR-IR) within the foetal subplate. Pregnant rats were made hypothyroid by the administration of methimazole and potassium perchlorate in drinking water. Maternal hypothyroidism significantly decreased PR-IR within the foetal subplate. Using the incorporation of 5-bromo-2'-deoxyuridine (BrDU) during subplate cell neurogenesis (embryonic day 13.5) to determine subplate cell survival in hypothyroid animals, we found that decreases in PR-IR cannot be attributed to significant subplate cell loss but are more likely the result of altered PR expression. Gestational thyroxine replacement to hypothyroid dams prevented the decrease in PR-IR within the subplate. These results identify thyroid hormone as a potential factor in the regulation of PR expression in the developing brain. These results are consistent with the idea that endocrine cross-talk between progesterone and thyroid hormone may be one mechanism by which maternal hypothyroidism alters normal cortical development. © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.

  13. Sex-Dependent, Osteoblast Stage-Specific Effects of Progesterone Receptor on Bone Acquisition.

    Science.gov (United States)

    Zhong, Zhendong A; Kot, Alexander; Lay, Yu-An E; Zhang, Hongliang; Jia, Junjing; Lane, Nancy E; Yao, Wei

    2017-09-01

    The role of the progesterone receptor (PR) in the regulation of sexual dimorphism in bone has yet to be determined. Here we utilized genetic fate mapping and Western blotting to demonstrate age-dependent PR expression in the mouse femoral metaphysis and diaphysis. To define sex-dependent and osteoblast stage-specific effects of PR on bone acquisition, we selectively deleted PR at different stages of osteoblast differentiation. We found that when Prx1-Cre mice were crossed with PR floxed mice to generate a mesenchymal stem cell (MSC) conditional KO model (Prx1; PRcKO), the mutant mice developed greater trabecular bone volume with higher mineral apposition rate and bone formation. This may be explained by increased number of MSCs and greater osteogenic potential, particularly in males. Age-related trabecular bone loss was similar between the Prx1; PRcKO mice and their WT littermates in both sexes. Hormone deficiency during the period of rapid bone growth induced rapid trabecular bone loss in both the WT and the Prx1; PRcKO mice in both sexes. No differences in trabecular bone mass was observed when PR was deleted in mature osteoblasts using osteocalcin-Cre (Bglap-Cre). Also, there were no differences in cortical bone mass in all three PRcKO mice. In conclusion, PR inactivation in early osteoprogenitor cells but not in mature osteoblasts influenced trabecular bone accrual in a sex-dependent manner. PR deletion in osteoblast lineage cells did not affect cortical bone mass. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  14. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2.

    Science.gov (United States)

    Lakhani, Sunil R; Van De Vijver, Marc J; Jacquemier, Jocelyne; Anderson, Thomas J; Osin, Peter P; McGuffog, Lesley; Easton, Douglas F

    2002-05-01

    The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes. Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein. Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls. BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harboring a germline mutation in BRCA1. The BRCA2 phenotype is currently not well defined.

  15. Obesity and overfeeding affecting both tumor and systemic metabolism activates the progesterone receptor to contribute to postmenopausal breast cancer

    Science.gov (United States)

    Giles, Erin D.; Wellberg, Elizabeth A.; Astling, David P.; Anderson, Steven M.; Thor, Ann D.; Jindal, Sonali; Tan, Aik-Choon; Schedin, Pepper S.; MacLean, Paul S.

    2014-01-01

    Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight-gain may provide a lifecycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake and proliferation markers. Treatment with the anti-diabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast

  16. Obesity and overfeeding affecting both tumor and systemic metabolism activates the progesterone receptor to contribute to postmenopausal breast cancer.

    Science.gov (United States)

    Giles, Erin D; Wellberg, Elizabeth A; Astling, David P; Anderson, Steven M; Thor, Ann D; Jindal, Sonali; Tan, Aik-Choon; Schedin, Pepper S; Maclean, Paul S

    2012-12-15

    Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight gain may provide a life cycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake, and proliferation markers. Treatment with the antidiabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast

  17. Progesterone withdrawal increases the α4 subunit of the GABAA receptor in male rats in association with anxiety and altered pharmacology — a comparison with female rats

    OpenAIRE

    Gulinello, M.; Gong, Q. H.; Smith, S. S.

    2002-01-01

    Withdrawal from the neurosteroid 3α,5α-allopregnanolone after chronic administration of progesterone increases anxiety in female rats and up-regulates the α4 subunit of the GABAA receptor (GABAA-R) in the hippocampus. We investigated if these phenomena would also occur in male rats. Progesterone withdrawal (PWD) induced higher α4 subunit expression in the hippocampus of both male and female rats, in association with increased anxiety (assessed in the elevated plus maze) comparable to effects ...

  18. Cell-specific localization of progesterone receptors in the bovine ovary at different stages of the oestrous cycle.

    Science.gov (United States)

    D'Haeseleer, M; Simoens, P; Van den Broeck, W

    2007-04-01

    This immunohistochemical study describes the localization of progesterone receptors (PR) in the bovine ovary of 23 cows at different stages of the oestrous cycle. In primordial, primary and secondary follicles the score for PR in the follicle cells increased progressively with the maturation of the follicle. In vital tertiary follicles and cystic atretic follicles a moderate score for PR was found, while in obliterative atretic follicles the score was much lower. Scores were high in corpora hemorrhagica, low in corpora lutea and still lower in corpora albicantia. Low PR scores were also found in the tunica albuginea and surface epithelium. Cyclic variations of PR immunoreactivity were manifest in most ovarian tissues. Follicular scores for PR were high in oestrus and decreased during the following stages, whereas scores in corpora lutea cells varied according to a characteristic pattern with high levels during oestrus and metoestrus. The variations in the scores for PR in the different ovarian cell types suggest a cell-specific and cycle-dependent influence of progesterone. A negative correlation was found between the PR scores and the plasma progesterone concentration.

  19. 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, Marianne; Sørensen, Flemming Brandt; Knudsen, Helle

    2008-01-01

    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....... End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec-as both ER-and PgR-. The four subgroups were Rec+/HER-2-, Rec...... after PMRT were found for ER-and PgR-tumors compared with the ER+ and PgR+ tumors (P = .003 and .04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec+/HER-2-subtype. CONCLUSION: Hormonal receptor status, HER-2, and the constructed...

  20. Progesterone withdrawal increases the α4 subunit of the GABAA receptor in male rats in association with anxiety and altered pharmacology — a comparison with female rats

    Science.gov (United States)

    Gulinello, M.; Gong, Q. H.; Smith, S. S.

    2010-01-01

    Withdrawal from the neurosteroid 3α,5α-allopregnanolone after chronic administration of progesterone increases anxiety in female rats and up-regulates the α4 subunit of the GABAA receptor (GABAA-R) in the hippocampus. We investigated if these phenomena would also occur in male rats. Progesterone withdrawal (PWD) induced higher α4 subunit expression in the hippocampus of both male and female rats, in association with increased anxiety (assessed in the elevated plus maze) comparable to effects previously reported. Because α4-containing GABAA-R are insensitive to the benzodiazepine (BDZ) lorazepam (LZM), and are positively modulated by flumazenil (FLU, a BDZ antagonist), we therefore tested the effects of these compounds following PWD. Using whole-cell patch clamp techniques, LZM-potentiation of GABA (EC20)-gated current was markedly reduced in CA1 pyramidal cells of male rats undergoing PWD compared to controls, whereas FLU had no effect on GABA-gated current in control animals but increased it in PWD animals. Behaviorally, both male and female rats were significantly less sensitive to the anxiolytic effects of LZM. In contrast, FLU demonstrated significant anxiolytic effects following PWD. These data suggest that neurosteroid regulation of the α4 GABAA-R subunit may be a relevant mechanism underlying anxiety disorders, and that this phenomenon is not sex-specific. PMID:12367616

  1. Progesterone withdrawal increases the alpha4 subunit of the GABA(A) receptor in male rats in association with anxiety and altered pharmacology - a comparison with female rats.

    Science.gov (United States)

    Gulinello, M; Gong, Q H; Smith, S S

    2002-09-01

    Withdrawal from the neurosteroid 3alpha,5alpha-allopregnanolone after chronic administration of progesterone increases anxiety in female rats and up-regulates the alpha4 subunit of the GABA(A) receptor (GABA(A)-R) in the hippocampus. We investigated if these phenomena would also occur in male rats. Progesterone withdrawal (PWD) induced higher alpha4 subunit expression in the hippocampus of both male and female rats, in association with increased anxiety (assessed in the elevated plus maze) comparable to effects previously reported. Because alpha4-containing GABA(A)-R are insensitive to the benzodiazepine (BDZ) lorazepam (LZM), and are positively modulated by flumazenil (FLU, a BDZ antagonist), we therefore tested the effects of these compounds following PWD. Using whole-cell patch clamp techniques, LZM-potentiation of GABA ((EC20))-gated current was markedly reduced in CA1 pyramidal cells of male rats undergoing PWD compared to controls, whereas FLU had no effect on GABA-gated current in control animals but increased it in PWD animals. Behaviorally, both male and female rats were significantly less sensitive to the anxiolytic effects of LZM. In contrast, FLU demonstrated significant anxiolytic effects following PWD. These data suggest that neurosteroid regulation of the alpha4 GABA(A)-R subunit may be a relevant mechanism underlying anxiety disorders, and that this phenomenon is not sex-specific.

  2. Gene and protein expression of oestrogen-β and progesterone receptors in facial melasma and adjacent healthy skin in women.

    Science.gov (United States)

    Tamega, A de A; Miot, H A; Moço, N P; Silva, M G; Marques, M E A; Miot, L D B

    2015-04-01

    Compare gene and protein expression for oestrogen receptor-β (ER-β) and progesterone receptor (PR) in facial melasma and adjacent healthy skin. A cross-sectional study including 42 women with facial melasma, conducted at the Dermatology Service of Botucatu Medical School of São Paulo State University, Brazil. Biopsies of the melasma skin were performed, together with healthy surrounding skin. The gene expression (real-time PCR) of the hormone receptors in the tissue was evaluated. Subsequently, skin fragments were immunostained for nuclear ER-β and PR, evaluated according to their HSCORE (epidermis) and percentage of staining per microscopic field (dermis). Messenger RNA tissue expression for ER-β and PR showed no difference between melasma-affected skin fragments and the healthy perilesional areas (P > 0.2). Median nuclear epithelial expression for ER-β and PR was higher in lesioned skin (HSCORE 157 and 58) than in the healthy perilesional skin (HSCORE 97 and 19; P expression for ER-β was associated to sun-induced melasma and negative familiar background; PR expression was associated to sun-induced melasma and darker phototypes. No difference was observed in gene expression for oestrogen-β and progesterone receptors in melasma-affected skin compared with adjacent healthy skin. However, the higher protein expression of these receptors in melasma-affected epithelia suggests hormonal participation in the pathogenesis of this disease. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  3. The ERα coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium

    Directory of Open Access Journals (Sweden)

    Howard Beatrice A

    2010-06-01

    Full Text Available Abstract The HER4 intracellular domain (4ICD is a potent estrogen receptor (ERα coactivator with activities in breast cancer and the developing mammary gland that appear to overlap with progesterone receptor (PgR. In fact, 4ICD has recently emerged as an important regulator and predictor of tamoxifen response, a role previously thought to be fulfilled by PgR. Here we investigated the possibility that the 4ICD coactivator regulates PgR expression thereby providing a mechanistic explanation for their partially overlapping activities in breast cancer. We show that 4ICD is both sufficient and necessary to potentiate estrogen stimulation of gene expression. Suppression of HER4/4ICD expression in the MCF-7 breast tumor cell line completely eliminated estrogen stimulated expression of PgR. In addition, the HER4/4ICD negative MCF-7 variant, TamR, failed to express PgR in response to estrogen. Reintroduction of wild-type HER4 but not the γ-secretase processing mutant HER4V673I into the TamR cell line restored PgR expression indicating that 4ICD is an essential PgR coactivator in breast tumor cells. These results were substantiated in vivo using two different physiologically relevant experimental systems. In the mouse mammary gland estrogen regulates expression of PgR-A whereas expression of PgR-B is estrogen independent. Consistent with a role for 4ICD in estrogen regulated PgR expression in vivo, PgR-A, but not PgR-B, expression was abolished in HER4-null mouse mammary glands during pregnancy. Coexpression of PgR and 4ICD is also commonly observed in ERα positive breast carcinomas. Using quantitative AQUA IHC technology we found that 4ICD potentiated PgR expression in primary breast tumors and the highest levels of PgR expression required coexpression of ERα and the 4ICD coactivator. In summary, our results provide compelling evidence that 4ICD is a physiologically important ERα coactivator and 4ICD cooperates with ERα to potentiate PgR expression

  4. A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A Partner and Regulator of Ferrochelatase.

    Science.gov (United States)

    Piel, Robert B; Shiferaw, Mesafint T; Vashisht, Ajay A; Marcero, Jason R; Praissman, Jeremy L; Phillips, John D; Wohlschlegel, James A; Medlock, Amy E

    2016-09-20

    Heme is an iron-containing cofactor essential for multiple cellular processes and fundamental activities such as oxygen transport. To better understand the means by which heme synthesis is regulated during erythropoiesis, affinity purification coupled with mass spectrometry (MS) was performed to identify putative protein partners interacting with ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway. Both progesterone receptor membrane component 1 (PGRMC1) and progesterone receptor membrane component 2 (PGRMC2) were identified in these experiments. These interactions were validated by reciprocal affinity purification followed by MS analysis and immunoblotting. The interaction between PGRMC1 and FECH was confirmed in vitro and in HEK 293T cells, a non-erythroid cell line. When cells that are recognized models for erythroid differentiation were treated with a small molecule inhibitor of PGRMC1, AG-205, there was an observed decrease in the level of hemoglobinization relative to that of untreated cells. In vitro heme transfer experiments showed that purified PGRMC1 was able to donate heme to apo-cytochrome b5. In the presence of PGRMC1, in vitro measured FECH activity decreased in a dose-dependent manner. Interactions between FECH and PGRMC1 were strongest for the conformation of FECH associated with product release, suggesting that PGRMC1 may regulate FECH activity by controlling heme release. Overall, the data illustrate a role for PGRMC1 in regulating heme synthesis via interactions with FECH and suggest that PGRMC1 may be a heme chaperone or sensor.

  5. Prostaglandin treatment is associated with a withdrawal of progesterone and androgen at the receptor level in the uterine cervix

    Science.gov (United States)

    Vladic-Stjernholm, Ylva; Vladic, Tomislav; Blesson, Chellakkan S; Ekman-Ordeberg, Gunvor; Sahlin, Lena

    2009-01-01

    Treatment with prostaglandin(PG)-E2 is clinically efficient for cervical priming. The aim of this study was to evaluate the impact of PG-E2 on the expression of the progesterone (PR), androgen (AR) and glucocorticoid (GR) receptors in human uterine cervix in prolonged pregnancy. The study groups were postterm nulliparous women with unripe cervices undergoing cervical priming with PG-E2 before labor induction. Responders (n = 12) who delivered vaginally were compared with non-responders (n = 10), who underwent cesarean section due to failure to progress to the active phase of labor. Controls (n = 18) with vaginal partus at a normal gestational age served as a reference group. Cervical levels of PR-A and PR- B isoforms, AR and GR, serum levels of their ligands and sex hormone-binding globulin (SHBG) were quantified. The responder group displayed lower total PR-AB and AR protein levels as compared to non-responders, and lower PR-B and AR protein levels as compared to controls. In addition, the PR mRNA level was lower in responders as compared to non-responders. The GR protein level did not differ between the groups. We conclude that successful PG-E2 priming was followed by a progesterone and androgen withdrawal at the receptor level in the uterine cervix. PMID:19852793

  6. Prostaglandin treatment is associated with a withdrawal of progesterone and androgen at the receptor level in the uterine cervix

    Directory of Open Access Journals (Sweden)

    Ekman-Ordeberg Gunvor

    2009-10-01

    Full Text Available Abstract Treatment with prostaglandin(PG-E2 is clinically efficient for cervical priming. The aim of this study was to evaluate the impact of PG-E2 on the expression of the progesterone (PR, androgen (AR and glucocorticoid (GR receptors in human uterine cervix in prolonged pregnancy. The study groups were postterm nulliparous women with unripe cervices undergoing cervical priming with PG-E2 before labor induction. Responders (n = 12 who delivered vaginally were compared with non-responders (n = 10, who underwent cesarean section due to failure to progress to the active phase of labor. Controls (n = 18 with vaginal partus at a normal gestational age served as a reference group. Cervical levels of PR-A and PR- B isoforms, AR and GR, serum levels of their ligands and sex hormone-binding globulin (SHBG were quantified. The responder group displayed lower total PR-AB and AR protein levels as compared to non-responders, and lower PR-B and AR protein levels as compared to controls. In addition, the PR mRNA level was lower in responders as compared to non-responders. The GR protein level did not differ between the groups. We conclude that successful PG-E2 priming was followed by a progesterone and androgen withdrawal at the receptor level in the uterine cervix.

  7. Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice

    Directory of Open Access Journals (Sweden)

    Baskin Laurence S

    2006-02-01

    Full Text Available Abstract Background Vinclozolin is a fungicide that has been reported to have anti-androgenic effects in rats. We have found that in utero exposure to natural or synthetic progesterones can induce hypospadias in mice, and that the synthetic progesterone medroxyprogesterone acetate (MPA feminizes male and virilizes female genital tubercles. In the current work, we selected a relatively low dose of vinclozolin to examine its in utero effects on the development of the genital tubercle, both at the morphological and molecular levels. Methods We gave pregnant dams vinclozolin by oral gavage from gestational days 13 through 17. We assessed the fetal genital tubercles from exposed fetuses at E19 to determine location of the urethral opening. After determination of gonadal sex, either genital tubercles were harvested for mRNA quantitation, or urethras were injected with a plastic resin for casting. We analyzed quantified mRNA levels between treated and untreated animals for mRNA levels of estrogen receptors α and β, progesterone receptor, and androgen receptor using nonparametric tests or ANOVA. To determine effects on urethral length (males have long urethras compared to females, we measured the lengths of the casts and performed ANOVA analysis on these data. Results Our morphological results indicated that vinclozolin has morphological effects similar to those of MPA, feminizing males (hypospadias and masculinizing females (longer urethras. Because these results reflected our MPA results, we investigated the effects of in utero vinclozolin exposure on the mRNA expression levels of androgen, estrogen α and β, and progesterone receptors. At the molecular level, vinclozolin down-regulated estrogen receptor α mRNA in females and up-regulated progesterone receptor mRNA. Vinclozolin-exposed males exhibited up-regulated estrogen receptor α and progesterone receptor mRNA, effects we have also seen with exposure to the synthetic estrogen, ethinyl

  8. In vivo phosphorylation of progesterone receptors in the T47D sub co human breast cancer cell line

    Energy Technology Data Exchange (ETDEWEB)

    Sheridan, P.L.

    1989-01-01

    We have had evidence indicating that human progesterone receptors (PR) are phosphoproteins, and used metabolic labeling with ({sup 35}S)methionine and ({sup 32}P)orthophosphate to study the synthesis, structure, and phosphorylation of PR in T47D{sub co} human breast cancer cells, a cell line extremely rich for PR. Human PR exist as two independent hormone-binding proteins; B-receptors which are triplets in SDS-gels (M{sub r} 114, 117, and 120 kDa), and A-receptors that are a single band (94 kDa). The work presented here documents that human A- and B-receptors are phosphorylated on serine residues in the untransformed state, with phosphate being incorporated into all three bands of the B-proteins. However, a brief ({sup 35}S)methionine pulse shows that both A and B are synthesized as singlets of 94 and 114 kDa, respectively. The B-triplet is formed post-translationally by slow phosphorylation. B-triplet formation, or maturation, can be reversed by treatment with calf alkaline phosphatase or stabilized by the presence of phosphatase inhibitors. Additional ({sup 35}S)labeling studies in the presence of progestins demonstrate that receptors that are 15 min old are able to bind hormone and transform to the tight nuclear binding state.

  9. A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization.

    Directory of Open Access Journals (Sweden)

    Ana C Mestre-Citrinovitz

    Full Text Available Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone and estrogen receptor (ICI182780 antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets.

  10. Hypothalamic effects of progesterone on regulation of the pulsatile and surge release of luteinising hormone in female rats.

    Science.gov (United States)

    He, Wen; Li, Xiaofeng; Adekunbi, Daniel; Liu, Yali; Long, Hui; Wang, Li; Lyu, Qifeng; Kuang, Yanping; O'Byrne, Kevin T

    2017-08-14

    Progesterone can block the oestradiol-induced GnRH/LH surge and inhibit LH pulse frequency. Recent studies reported that progesterone prevented premature LH surges during ovarian hyperstimulation in women. As the most potent stimulator of GnRH/LH release, kisspeptin is believed to mediate the positive and negative feedback effects of oestradiol in the hypothalamic anteroventral periventricular (AVPV) and arcuate (ARC) nuclei, while the region-specific role of progesterone receptors in these nuclei remains unknown. This study examined the hypothesis that progesterone inhibits LH surge and pulsatile secretion via its receptor in the ARC and/or AVPV nuclei. Adult female rats received a single injection of pregnant mare serum gonadotropin followed by progesterone or vehicle. Progesterone administration resulted in a significant prolongation of the oestrous cycle and blockade of LH surge. However, microinjection of the progesterone receptor antagonist, RU486, into the AVPV reversed the prolonged cycle length and rescued the progesterone blockade LH surge, while RU486 into the ARC shortened LH pulse interval in the progesterone treated rats. These results demonstrated that progesterone's inhibitory effect on the GnRH/LH surge and pulsatile secretion is mediated by its receptor in the kisspeptin enriched hypothalamic AVPV and ARC respectively, which are essential for progesterone regulation of oestrous cyclicity in rats.

  11. A Survey of the Relationship between Serum Testosterone Level and Expressions of Androgen, Progesterone and Estrogen Receptors and HER2 in Iranian Women with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Reza Vojdani

    2015-07-01

    Full Text Available Background: Breast cancer is the most common cause of cancer in women. This tumor is hormone dependent tumor and oncologists use estrogen receptor (ER, progesterone receptor (PR and HER2 for treatment of this malignancy. Androgens like testosterone and their receptors (AR have a role in the pathophysiology of breast cancer but their clinical values are not clear. Method: AR expression was evaluated in 49 patients with breast cancers using immunohistochemistry. Testosterone was evaluated with ELISA. The relation of clinical characteristics and biomarkers with AR and testosterone were analyzed. According to the percentage of stained cells AR categorized to: AR-absent (0%, AR-poorly (1%-10%, AR-moderately (>10%-50%, and AR-highly (>50% positive. Results: Among 49 patients with breast cancer, 34% were AR-positive and 44% of ERpositive and 22% of ER negative patients were AR-positive. There was no significant association between mean of testosterone and AR, ER, PR and HER2. AR was positive more frequently but not significantly statistically in older patients and patients less than 45 years of age. Testosterone level was higher in ER positive patients than ER negative and lower in AR positive patients than AR negative patients, but these findings were not statistically significant. ten persent of breast cancers were triple negative and AR was negative in all of them. Conclusion: Androgens and AR have role in pathophysiology of breast cancer and in the future one can use the potency of this pathway for the treatment of breast cancer.

  12. Progesterone as an immunomodulatory molecule.

    Science.gov (United States)

    Szekeres-Bartho, J; Barakonyi, A; Par, G; Polgar, B; Palkovics, T; Szereday, L

    2001-06-01

    Increased progesterone sensitivity of pregnancy lymphocytes is due to activation-induced appearance of progesterone binding sites in the lymphocytes. Following recognition of fetally derived antigens gamma/delta TCR+ cells develop progesterone receptors. Progesterone binding results in the synthesis of a mediator protein named the progesterone-induced blocking factor (PIBF). PIBF by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling NK activity exerts an anti-abortive effect.

  13. 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...

  14. Oral progesterone decreases saccadic eye velocity and increases sedation in women.

    NARCIS (Netherlands)

    Broekhoven, F. van; Backstrom, T.; Verkes, R.J.

    2006-01-01

    The aim of this study was to investigate the neurophysiological and behavioural effects of a single dose of progesterone in women. Allopregnanolone is a metabolite of progesterone and a potent positive modulator of the GABA(A) receptor and produces sedative and anxiolytic effects. This study was

  15. X-ray structures of progesterone receptor ligand binding domain in its agonist state reveal differing mechanisms for mixed profiles of 11beta-substituted steroids.

    NARCIS (Netherlands)

    Lusher, S.J.; Raaijmakers, H.C.A.; Vu-Pham, D.; Kazemier, B.; Bosch, R.; McGuire, R.; Azevedo, R.; Hamersma, H.; Dechering, K.; Oubrie, A.; Duin, M. van; Vlieg, J. de

    2012-01-01

    We present here the x-ray structures of the progesterone receptor (PR) in complex with two mixed profile PR modulators whose functional activity results from two differing molecular mechanisms. The structure of Asoprisnil bound to the agonist state of PR demonstrates the contribution of the ligand

  16. Effect of the Novel Selective Progesterone Receptor Modulator Vilaprisan on Ovarian Activity in Healthy Women.

    Science.gov (United States)

    Schütt, Barbara; Schultze-Mosgau, Marcus-Hillert; Draeger, Corinna; Chang, Xinying; Löwen, Stephanie; Kaiser, Andreas; Rohde, Beate

    2017-09-21

    This randomized, double-blind, parallel-group study in healthy young women investigated the effect of treatment with vilaprisan (0.5, 1, 2, or 4 mg/day for 12 weeks) on ovarian function by assessing the Hoogland score, which is based on the size of follicle-like structures as determined by transvaginal ultrasound and on estradiol and progesterone serum concentrations. Ovulation inhibition (ie, Hoogland score 80% of the subjects receiving vilaprisan ≥1 mg/day. The effect was dose dependent. With a Bayesian approach, the percentage of subjects with ovulation inhibition was estimated to increase from 37% in subjects receiving 0.5 mg/day vilaprisan to 76%, 86%, and 88% in subjects receiving 1, 2, and 4 mg/day, respectively. Follicle growth was not suppressed during treatment. The majority of subjects receiving ≥1 mg/day had a Hoogland score of 4 (active follicle-like structures, ie, follicle diameter >13 mm, estradiol >27.2 pg/mL, no progesterone increase) both at beginning and end of treatment. Mean average estradiol as well as mean maximum progesterone concentrations were noticeably decreased during treatment with vilaprisan ≥1 mg/day compared to pretreatment, but estradiol concentrations remained >80 pg/mL. Both hormones returned to pretreatment levels after the end of treatment, indicating a rapid resumption of normal ovarian activity. Amenorrhea occurred in the majority of subjects during treatment at dosages ≥1 mg/day. The adverse events observed in this study confirm the known safety profile of vilaprisan. All in all, the results of this study support the development of vilaprisan for the long-term treatment of uterine fibroids. © 2017, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  17. 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

  18. Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone.

    Science.gov (United States)

    Kannan, Athilakshmi; Bhurke, Arpita; Sitruk-Ware, Regine; Lalitkumar, Parameswaran G; Gemzell-Danielsson, Kristina; Williams, Alistair R W; Taylor, Robert N; Bagchi, Milan K; Bagchi, Indrani C

    2017-01-01

    Ulipristal acetate (UPA) is a selective progesterone receptor modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives-expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound progesterone receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use.

  19. Ligand-controlled interaction of histone acetyltransferase binding to ORC-1 (HBO1) with the N-terminal transactivating domain of progesterone receptor induces steroid receptor coactivator 1-dependent coactivation of transcription

    NARCIS (Netherlands)

    M. Georgiakaki (Maria); L.J. Blok (Leen); R. Milgrom (Roni); M. Lombès (Marc); A. Guiochon-Mantel (Anne); H. Loosfelt (Hugues); N. Chabbert-Buffet (Nathalie); B. Dasen (Boris); G. Meduri (Geri); S. Wenk (Sandra); L. Rajhi (Leila); L. Amazit (Larbi); A. Chauchereau (Anne); C.W. Burger (Curt)

    2006-01-01

    textabstractModulators of cofactor recruitment by nuclear receptors are expected to play an important role in the coordination of hormone-induced transactivation processes. To identify such factors interacting with the N-terminal domain (NTD) of the progesterone receptor (PR), we used this domain as

  20. Immunohistochemical evaluation of estrogen and progesterone receptors in peripheral and central giant cell granuloma of the jaws

    Directory of Open Access Journals (Sweden)

    Razavi SM

    2006-07-01

    Full Text Available Background and Aim: Giant cell granuloma is a relatively common benign proliferative lesion of the oral cavity. This lesion has a marked gender predilection with more prevalence in females and tendency to rapid growth and recurrence during pregnancy. The aim of this study was the evaluation of specific receptors of sex hormones in giant cell granuloma. Materials and Methods: In this cross-sectional study, twenty five cases of formalin fixed paraffin embedded giant cell granulomas were retrieved from the oral pathology archive of dental school Isfahan University of Medical Sciences. Also twenty five normal oral mucosa biopsies resected during different surgical procedures were prepared as control group. Cases were immunohistochemically stained for estrogen and progesterone receptors using the biotin-streptavidine method. Data were analyzed by SPSS package. Results: Staining for ER/PR markers were negative for the mononuclear stromal cells and multinucleated giant cells in all cases. The epithelial cells and connective tissue stromal cells of the control group were also negative for these receptors. Conclusion: Based on the results of this study, immunostaining for ER/PR was negative in all cases. These findings suggest that in most cases development and growth of this lesion is not directly related to these hormones. However further studies with more sensitive techniques are recommended.

  1. Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis

    DEFF Research Database (Denmark)

    Pearce, C.L.; Wu, A.H.; Gayther, S.A.

    2008-01-01

    analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases......There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone...... receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR...

  2. Levels of estrogen receptor B splice variant (ERBΔ5 mRNA correlates with progesterone receptor in breast carcinomas

    Directory of Open Access Journals (Sweden)

    Mandušić Vesna

    2010-01-01

    Full Text Available It is well known that breast tumors which are estrogen positive ER(+ are more likely to respond to hormone therapy. However, a certain percentage of ER(+/PR(+ tumors do not respond to this therapy. Identification of the second estrogen receptor, named estrogen receptor beta (ERβ, as well as the existence of numerous isoforms/splice variants of both ERα and ERβ, suggests that a complex regulation of estrogen action exists. In this study, we analyzed the expression ratio of ERβ1 isoform and ERβΔ5 splice variant mRNAs, and its correlation with ER/PR status by quantitative RT-PCR and clinical and histopathological parameters. We found that the relative proportion of ERβΔ5 in the total ERβ1 transcript 'pool' inversely correlates with the PR level (p = -0,359, p< 0,003, Spearman. It may be that the ERβΔ5 variant modulates the ERα activity of downstream targets. In addition, we suggest that the determination of the expression profiles of ERα and ERβ isoforms and splice variants in the defined groups of patients are necessary for elucidating their involvement in endocrine resistance.

  3. Polymorphism in CYP17, GSTM1 and the progesterone receptor genes and its relationship with mammographic density

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    D. Chambo

    2009-04-01

    Full Text Available Radiologic breast density is one of the predictive factors for breast cancer and the extent of the density is directly related to postmenopause. However, some patients have dense breasts even during postmenopause. This condition may be explained by the genes that codify for the proteins involved in the biosynthesis, as well as the activity and metabolism of steroid hormones. They are polymorphic, which could explain the variations of individual hormones and, consequently, breast density. The constant need to find markers that may assist in the primary prevention of breast cancer as well as in selecting high risk patients motived this study. We determined the influence of genetic polymorphism of CYP17 (cytochrome P450c17, the gene involved in steroid hormone biosynthesis, GSTM1 (glutathione S-transferase M1, an enzyme involved in estrogen metabolism and PROGINS (progesterone receptor, for association with high breast density. One hundred and twenty-three postmenopausal patients who were not on hormone therapy and had no clinical or mammographic breast alterations were included in the present study. The results of this study reveal that there was no association between dense breasts and CYP17 or GSTM1. There was a trend, which was not statistically significant (P = 0.084, towards the association between PROGINS polymorphism and dense breasts. However, multivariate logistic regression showed that wild-type PROGINS and mutated CYP17, taken together, resulted in a 4.87 times higher chance of having dense breasts (P = 0.030. In conclusion, in the present study, we were able to identify an association among polymorphisms, involved in estradiol biosyntheses as well as progesterone response, and radiological mammary density.

  4. The presence and role of progesterone receptor in the ovaries of postmenopausal women who have not applied hormone replacement therapy.

    Directory of Open Access Journals (Sweden)

    Małgorzata Piasecka

    2008-12-01

    Full Text Available At present, not much is known about progesterone receptor (PR expression and localization in postmenopausal women ovaries. In the ovaries of reproductive age women, PR is localized in internal theca and granulosa cells, corpus luteum, ovary surface epithelium (OSE and in stroma. PR expression depends on the serum concentration of progesterone, estrogen, gonadotropin and androgen. The goal of the conducted studies was to examine PR localization and expression in the ovaries of postmenopausal women who have not applied hormone replacement therapy so far. Also, the correlation was examined between PR expression and localization in the ovaries, steroid and gonadotropin hormone serum concentrations, and influence of the time from the last menstruation. The material came from 50 postmenopausal women who had their ovaries removed due to non-neoplastic diseases. The women were divided into 3 groups (A, B, C depending on the time from the last menstruation. The follitropin (FSH, luteotropin (LH, estradiol (E2, testosterone (T, androstendione (A and dehydroepiandrosterone sulphate (DHEAS concentrations in blood plasma were measured. Monoclonal mouse anti-human PR antibody was used for immunohistochemical detection (examination involved 50 postmenopausal ovaries. Between particular groups, E2 serum concentrations did not differ, but FSH, LH, T, A, DHEAS serum concentrations were significantly different. Immunohistochemical nuclear localization of PR in postmenopausal women ovaries was observed. PR expression was similar in all three groups (A, B, C. PR expression was observed in OSE nuclei and invaginations cysts deriving from the isolation of invaginated epithelium and metaplastic columnar epithelium and in stroma. In the ovaries of postmenopausal women who have not applied hormone replacement therapy so far, PR was detected in all three groups. Its expression did not depend on the time from menopause and was similar in all examined groups. FSH, LH, T, A

  5. Uterine and placental expression of TRPV6 gene is regulated via progesterone receptor- or estrogen receptor-mediated pathways during pregnancy in rodents

    Directory of Open Access Journals (Sweden)

    Choi Kyung-Chul

    2009-05-01

    Full Text Available Abstract Transient receptor potential cation channel, subfamily V, member 6 (TRPV6 is an epithelial Ca2+ channel protein expressed in calcium absorbing organs. In the present study, we investigated the expression and regulation of uterine and placental TRPV6 during gestation in rodents. Uterine TRPV6 peaked at pregnancy day (P 0.5, P5.5 and, P13.5 and was detected in uterine epithelium and glands of rats, while placental TRPV6 mRNA levels increased in mid-gestation. Uterine and placental TRPV6 mRNA levels in rats appear to cyclically change during pregnancy, suggesting that TRPV6 may participate in the implantation process. In addition, uterine TRPV6 mRNA is only expressed in placenta-unattached areas of the uterus, and uterine TRPV6 immunoreactivity was observed in luminal and glandular epithelial cells. In the placenta, TRPV6 was detected in the labyrinth and spongy zone. These results may indicate that TRPV6 has at least two functions: implantation of the embryo and maintenance of pregnancy. To investigate the pathway(s mediating TRPV6 expression in rodents, anti-steroid hormone antagonists were injected prior to maximal TRPV6 expression. In rats, TRPV6 expression was reduced by RU486 (an anti-progesterone through progesterone receptors, and ICI 182,780 (an anti-estrogen blocked TRPV6 expression via estrogen receptors in mice. The juxtaposition of uterine and placental TRPV6 expressed in these tissues supports the notion that TRPV6 participates in transferring calcium ions between the maternal and fetal compartments. Taken together, TRPV6 gene may function as a key element in controlling calcium transport in the uterus between the embryo and the placenta during pregnancy.

  6. Parturition induction in ewes by a progesterone receptor blocker, aglepristone, and subsequent neonatal survival: Preliminary results.

    Science.gov (United States)

    Özalp, R G; Yavuz, A; Orman, A; Seker, I; Udum Küçükşen, D; Rişvanlı, A; Demiral, Ö O; Wehrend, A

    2017-01-01

    The clinical effects of aglepristone treatment to induce parturition in ewes and their newborns were reported. Three experimental groups were defined: group AG5 (n = 5), group AG10 (n = 5), and group CG (n = 5) in which ewes were injected twice with 5, 10 mg/kg of aglepristone, and saline solution of ewes, respectively. Different parameters associated with parturition in ewes and their newborns were investigated. Serum progesterone, oxytocin, and free and conjugated total estrogens were measured after treatments until parturition. No statistical difference was found from first aglepristone administration to onset of lambing between AG5 and AG10 (23.90 ± 6.20, 40.00 ± 6.71 hours). Parturition induction in two groups shortened the gestational length significantly compared with the control group (P = 0.003). Dystocia was observed in two ewes in group AG10. The placental weight showed statistically significant difference only between the AG10 and CG (P = 0.039), but no difference was observed in the placental expulsion period between the groups. Decrease in food consumption 24 to 36 hours after parturition in all ewes and skin necrosis in an ewe in group AG5 were observed. Progesterone concentration was significantly lower in AG5 than that in ewes in group AG10 and CG (P birth weight (4.29 ± 0.28 kg), which was significantly different from the induced groups. No significant difference of blood pH and blood gases values between groups was identified both at birth and 12 hours after parturition for lambs. Significant differences could clearly be observed in total protein and blood urea nitrogen and total protein findings 12 hours after parturition (P control lambing time without any side effects in either mothers or lambs. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Progesterone antagonizes the positive influence of estrogen on Chlamydia trachomatis serovar E in an Ishikawa/SHT-290 co-culture model.

    Science.gov (United States)

    Kintner, Jennifer; Schoborg, Robert V; Wyrick, Priscilla B; Hall, Jennifer V

    2015-06-01

    Studies indicate that estrogen enhances Chlamydia trachomatis serovar E infection in genital epithelial cells. Hormones have direct and indirect effects on endometrial epithelial cells. Estrogen and progesterone exposure induces endometrial stromal cells to release effectors that subsequently regulate growth and maturation of uterine epithelial cells. Estrogen enhances C. trachomatis infection by aiding entry and intracellular development in endometrial epithelial cell (Ishikawa, IK)/SHT-290 stromal cell co-culture. Enhanced chlamydial infection was mediated by direct estrogen-stimulated signaling events in epithelial cells and indirectly via estrogen-induced stromal cell effectors. The current study investigates the effects of hormones on chlamydial development using culture conditions representative of the menstrual cycle. Chlamydia trachomatis-infected IK or IK/SHT-290 cultures were exposed to 10(-8) M estrogen (E2), 10(-7) M progesterone (P4) or a combination of both hormones (10(-8) M E2 followed by 10(-9) M E2/10(-7) M P4). Chlamydial infectivity and progeny production were significantly decreased (30-66%) in cultures exposed to progesterone or estrogen/progesterone combination compared to estrogen alone. Thus, progesterone antagonized the positive effects of estrogen on chlamydial infection. These data indicate the susceptibility of endometrial epithelial cells to C. trachomatis infection during the menstrual cycle is altered by phase specific actions of sex hormones in the genital tract. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Progesterone, estrogen, and androgen receptors in the corpus luteum of the domestic cat, Iberian lynx (Lynx pardinus) and Eurasian lynx (Lynx lynx).

    Science.gov (United States)

    Amelkina, Olga; Zschockelt, Lina; Painer, Johanna; Serra, Rodrigo; Villaespesa, Francisco; Krause, Eberhard; Jewgenow, Katarina; Braun, Beate C

    2016-12-01

    In contrast to the species studied, the corpus luteum (CL) of Iberian and Eurasian lynx physiologically persists in the ovary for more than 2 years and continues to secrete progesterone. Such persistent CL (perCL) transition into the next cycle and are present in the ovary together with the freshly formed CL (frCL) of a new ovulation. To date, the mechanisms supporting such CL persistence are not known. We analyzed the potential receptivity of feline CL to sex steroids through mRNA measurements of progesterone receptor (PGR), progesterone receptor membrane components (PGRMC) 1 and 2, estrogen receptor (ESR) 1 and ESR2, G protein-coupled estrogen receptor 1 (GPER1), and androgen receptor (AR). All receptors were present in domestic cat CL during pregnancy and the nonpregnant luteal phase, in frCL and perCL of post-mating Iberian lynx and in perCL of pre-mating Eurasian lynx. Mass spectrometry detected the presence of PGRMC1 protein in frCL and perCL of the Iberian lynx. In both domestic cat and lynx CL, PGR, PGRMC1, and ESR1 proteins were localized in luteal cells by immunohistochemistry. The mRNA levels of PGR, PGRMC1, PGRMC2, ESR1, and AR changed significantly throughout the domestic cat luteal phase. This may indicate involvement of these receptors in the processes of formation, maintenance, and regression of feline CL. In Iberian lynx, expression of PGRMC1, PGRCM2, ESR1, GPER1, and AR was significantly higher in perCL compared with frCL, whereas ESR2 was reversed. High mRNA amounts of these receptors in perCL suggest that physiological persistence of lynx CL may be partly regulated by actions of sex steroids through their nuclear and/or membrane receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Identification of oestrogen, progesterone receptor and human epidermal growth factor receptor 2 expression in mediastinal metastases of breast cancer obtained by endobronchial ultrasound-guided transbronchial needle aspiration.

    Science.gov (United States)

    Serra, P; Sanz-Santos, J; Castellà, E; Cirauqui, B; Andreo, F; Llatjós, M; Avila, M; Margelí, M; Serrano, L; Centeno, C; Quiroga, V; Torky, M; Ruiz-Manzano, J

    2017-11-09

    In breast cancer patients, the expression statuses of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are crucial in the choice of treatment. Receptor expression in metastatic lesions can differ from the primary tumour. The aim of our study was to analyse the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to obtain samples allowing the identification of ER, PR and HER2 expression in patients with mediastinal metastases of breast cancer. The clinical files of all patients with a final diagnosis of breast cancer mediastinal metastases diagnosed by EBUS-TBNA in our institution were retrospectively analysed. The ability of EBUS-TBNA to obtain samples that allowed hormone receptor and HER2 expression analysis was calculated. Twenty-four patients were included. ER, PR and HER2 assessments could be performed in 22, 20 and 22 patients, respectively. In 20 of the 24 patients it was possible to investigate all three types of receptor expression. In the remaining four cases, where ER, PR or HER2 expression tests could not be performed, it was due to a lack of tissue. In cases with adequate results for EBUS-TBNA and the primary tumour agreement was greater for ER (16/19) and HER2 (12/14) than PR (8/17). Based on receptor status, there was a change in the choice of treatment for five patients. In patients with breast cancer mediastinal metastases, ER, PR and HER2 expression can be assessed in samples obtained by EBUS-TBNA whenever a sufficient tissue sample is collected. © 2017 John Wiley & Sons Ltd.

  10. Ulipristal Acetate Antagonizes the Inhibitory Effect of Progesterone on Ciliary Beat Frequency and Upregulates Steroid Receptor Expression Levels in Human Fallopian Tubes.

    Science.gov (United States)

    Yuan, Jiangjing; Zhao, Weihong; Yan, Mingxing; Zhu, Qian; Qin, Guojuan; Qiu, Jun; Zhang, Jian

    2015-12-01

    Ulipristal acetate (UPA) is a new selective progesterone receptor (PR) modulator used for emergency contraception. However, our understanding of its mechanisms of action on oviductal cilia is limited. The present study focused on the in vitro effects of UPA (0.1, 1, and 10 μmol/L) on the cilia and steroid receptors of human fallopian tubes. The ciliary beat frequency (CBF), the ultrastructure of cilia, and the levels of steroid receptors were measured. The effects of UPA on the progesterone-induced CBF reduction were also studied. Our results show that UPA dose dependently antagonizes the progesterone-induced CBF decrease, but it does not affect the CBF or the ultrastructure of the cilia. The UPA also upregulates the expression levels of the estrogen receptor α and the PR in the fallopian tubes. The results enable us to better understand the mechanisms by which UPA works as an emergency contraceptive and provides a scientific basis for its clinical application. © The Author(s) 2015.

  11. Negative Conversion of Progesterone Receptor Status after Primary Systemic Therapy Is Associated with Poor Clinical Outcome in Patients with Breast Cancer.

    Science.gov (United States)

    Ahn, Soomin; Kim, Hyun Jeong; Kim, Milim; Chung, Yul Ri; Kang, Eunyoung; Kim, Eun-Kyu; Kim, Se Hyun; Kim, Yu Jung; Kim, Jee Hyun; Kim, In Ah; Park, So Yeon

    2018-01-24

    Alteration of biomarker status after primary systemic therapy (PST) is occasionally found in breast cancer. This study was conducted to clarify the clinical implications of change of biomarker status in breast cancer patients treated with PST. The pre-chemotherapeutic biopsy and post-chemotherapeutic resection specimens of 442 breast cancer patients who had residual disease after PST were included in this study. The association between changes of biomarker status after PST and clinicopathologic features of tumors, and survival of the patients, were analyzed. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status changed after PST in 18 (4.1%), 80 (18.1%), and 15 (3.4%) patients, respectively. ER and PR mainly underwent positive to negative conversion, whereas HER2 status underwent negative to positive conversion. Negative conversion of ER and PR status after PST was associated with reduced disease-free survival. Moreover, a decline in the Allred score for PR in post-PST specimens was significantly associated with poor clinical outcome of the patients. HER2 change did not have prognostic significance. In multivariate analyses, negative PR status after PST was found to be an independent adverse prognostic factor in the whole patient group, in the adjuvant endocrine therapy-treated subgroup, and also in pre-PST PR positive subgroup. ER and HER2 status changed little after PST, whereas PR status changed significantly. In particular, negative conversion of PR status was as a poor prognostic indicator, suggesting that re-evaluation of basic biomarkers is mandatory in breast cancer after PST for proper management and prognostication of patients.

  12. Evaluation of a cow-side milk progesterone assay and assessment of the positive predictive value of oestrus diagnosis by dairy farmers in New South Wales.

    Science.gov (United States)

    Ingenhoff, L; Hall, E; House, J K

    2016-12-01

    The three objectives of this study were to determine the positive predictive value (PPV) of oestrus diagnosis (heat detection accuracy) by dairy farmers, calculate the diagnostic sensitivity and specificity of the P4 Rapid milk progesterone assay for detecting a corpus luteum and evaluate the economics of using a cow-side milk progesterone assay designed to aid oestrus diagnosis. Milk samples were collected from 752 cows diagnosed in oestrus by farm personnel on 14 dairy farms. Samples were tested using the P4 Rapid milk progesterone assay to estimate the PPV of oestrus diagnosis at each farm and a crude pooled mean of PPV of oestrus diagnosis across all farms. A further 156 milk samples were collected from cows with luteal tissue status determined by transrectal ultrasound and tested by the P4 Rapid assay to enable calculation of the sensitivity and specificity of the P4 Rapid assay. For pooled farm samples, the PPV was 97.0%, with a range between farms of 88.9-100%. Sensitivity of the P4 Rapid milk progesterone assay for detecting a corpus luteum was 90.1% and specificity was 98.7%. Misclassification of oestrus in cows previously identified as pregnant was the most common cause of false-positive oestrus diagnoses by farm personnel. Routine testing of milk progesterone in all cows diagnosed in oestrus is not economically justified and may even slightly reduce submission rates; conversely, strategic use of cow-side milk progesterone assays can improve herd reproductive performance by facilitating decisions on whether to rebreed cows previously diagnosed as pregnant. © 2016 Australian Veterinary Association.

  13. Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Simian, Marina; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Shyamala, Gopalan

    2009-05-11

    Expression of the A and B forms of progesterone receptor (PR) in an appropriate ratio is critical for mammary development. Mammary glands of PR-A transgenic mice, carrying an additional A form of PR as a transgene, exhibit morphological features associated with the development of mammary tumors. Our objective was to determine the roles of estrogen (E) and progesterone (P) in the genesis of mammary hyperplasias/preneoplasias in PR-A transgenics. We subjected PR-A mice to hormonal treatments and analyzed mammary glands for the presence of hyperplasias and used BrdU incorporation to measure proliferation. Quantitative image analysis was carried out to compare levels of latency-associated peptide and transforming growth factor beta 1 (TGF{beta}1) between PR-A and PR-B transgenics. Basement membrane disruption was examined by immunofluorescence and proteolytic activity by zymography. The hyperplastic phenotype of PR-A transgenics is inhibited by ovariectomy, and is reversed by treatment with E + P. Studies using the antiestrogen ICI 182,780 or antiprogestins RU486 or ZK 98,299 show that the increase in proliferation requires signaling through E/estrogen receptor alpha but is not sufficient to give rise to hyperplasias, whereas signaling through P/PR has little impact on proliferation but is essential for the manifestation of hyperplasias. Increased proliferation is correlated with decreased TGF{beta}1 activation in the PR-A transgenics. Analysis of basement membrane integrity showed loss of laminin-5, collagen III and collagen IV in mammary glands of PR-A mice, which is restored by ovariectomy. Examination of matrix metalloproteases (MMPs) showed that total levels of MMP-2 correlate with the steady-state levels of PR, and that areas of laminin-5 loss coincide with those of activation of MMP-2 in PR-A transgenics. Activation of MMP-2 is dependent on treatment with E and P in ovariectomized wild-type mice, but is achieved only by treatment with P in PR-A mice. These data

  14. Quality assessment of estrogen receptor and progesterone receptor testing in breast cancer using a tissue microarray-based approach

    NARCIS (Netherlands)

    T.J.A. Dekker; S. ter Borg; J. Hooijer; S.L. Meijer (Sybren); J. Wesseling (Jelle); J.E. Boers (James); E. Schuuring; J. Bart; J. van Gorp (Joost); P. Bult (Peter); S. Riemersma (Sietske); C.H.M. van Deurzen (Carolien); H.F. Sleddens (Hein); W.E. Mesker; J.R. Kroep (Judith); V.T.H.B.M. Smit (Vincent); M.J. Vijver (Marc )

    2015-01-01

    textabstractAssessing hormone receptor status is an essential part of the breast cancer diagnosis, as this biomarker greatly predicts response to hormonal treatment strategies. As such, hormone receptor testing laboratories are strongly encouraged to participate in external quality control schemes

  15. Androgen, estrogen and progesterone receptor expression in the human uterus during the menstrual cycle

    NARCIS (Netherlands)

    Mertens, HJMM; Heineman, MJ; Theunissen, PHMH; de Jong, FH; Evers, JLH

    Cyclic changes in steroid receptor expression in endometrial cells are considered a reflection of its differential functions. Besides estrogen and progestogens, androgens have also been suggested to affect the biological function of the female reproductive tract. We investigated the distribution and

  16. The progesterone receptor PROGINS polymorphism is not related to oxidative stress factors in women with polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Saygili Fusun

    2007-10-01

    Full Text Available Abstract Background Women with PCOS have been reported to be at increased risk of a number of gynaecological neoplasias, including endometrial, breast, and ovarian cancer. Studies of the possible association of genetic variation in progesterone receptor polymorphism with risk of ovarian and breast cancer have concentrated on a variant known as PROGINS. Methods Ninety-five young women with PCOS and 99 healthy control women were included in our study. All subjects underwent venous blood drawing for complete hormonal assays, lipid profile, glucose, insulin and PROGINS polymorphism genetic study. Results In PROGINS polymorphism results; in both control and the patient groups T1/T1 has been detected in high levels. But for genotype (p = 0.178 and allele (p = 0.555 frequencies both of the groups give similar results. Statistically significant difference has been detected on serum FSH levels for T1/T1 genotype according to T2/T2 genotype. Conclusion No relation has been detected between the inflammatory and oxidative stress factors, and PROGINS polymorphism alleles. This may be because the PCOS patients are young and their BMI means are normal and their CIMT and oxidative stress markers are like healthy women.

  17. Stromal Progesterone Receptors Mediate Induction of Indian Hedgehog (IHH) in Uterine Epithelium and Its Downstream Targets in Uterine Stroma

    Science.gov (United States)

    Simon, Liz; Spiewak, Kerry A.; Ekman, Gail C.; Kim, Jaeyeon; Lydon, John P.; Bagchi, Milan K.; Bagchi, Indrani C.; DeMayo, Francesco J.; Cooke, Paul S.

    2009-01-01

    Uterine receptivity to embryo implantation depends on appropriate progesterone (P4) and estrogen stimulation. P4 rapidly stimulates production of the morphogen Indian hedgehog (IHH) in murine uterine epithelium as well as downstream molecules in the hedgehog pathway such as Patched homolog 1 (PTCH1) and nuclear receptor subfamily 2, group F, member 2 (NR2F2) in uterine stroma. Studies using IHH-null mice indicate that IHH is obligatory for the normal P4 response in the uterus. To determine whether IHH induction in uterine epithelium is mediated through P4 receptor (PR) in epithelium (E) and/or stroma (S), we produced tissue recombinants using uteri from neonatal PR knockout (ko) mice and wild-type (wt) mice containing PR in S and/or E or lacking PR altogether using a tissue recombinant methodology and assessed their response to P4. In tissue recombinants containing wt-S (wt-S + wt-E and wt-S + ko-E), P4 induced Ihh mRNA expression at 6 h that was 6-fold greater than in oil-treated controls (P < 0.05; n = 6) in both types of tissue recombinants despite the absence of epithelial PR in wt-S + ko-E grafts. Conversely, Ihh mRNA expression was unaffected by P4 in ko-S + ko-E and ko-S + wt-E grafts despite epithelial PR expression in the latter. Nr2f2 and Ptch1 mRNA expression was similar in that it was stimulated by P4 only in recombinants containing stromal PR. These results indicate that stromal PR is both necessary and sufficient for P4 stimulation of epithelial IHH as well as downstream events such as PTCH1 and NR2F2 increases in stroma. PMID:19372202

  18. Neurosteroid withdrawal regulates GABA-A receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway.

    Science.gov (United States)

    Gangisetty, O; Reddy, D S

    2010-10-27

    Neurosteroids regulate GABA-A receptor plasticity. Neurosteroid withdrawal occurs during menstruation and is associated with a marked increase in expression of GABA-A receptor α4-subunit, a key subunit linked to enhanced neuronal excitability, seizure susceptibility and benzodiazepine resistance. However, the molecular mechanisms underlying the upregulation of α4-subunit expression remain unclear. Here we utilized the progesterone receptor (PR) knockout mouse to investigate molecular pathways of PR and the transcription factor early growth response factor-3 (Egr3) in regulation of the GABA-A receptor α4-subunit expression in the hippocampus in a mouse neurosteroid withdrawal paradigm. Neurosteroid withdrawal induced a threefold increase in α4-subunit expression in wild-type mice, but this upregulation was unchanged in PR knockout mice. The expression of Egr3, which controls α4-subunit transcription, was increased significantly following neurosteroid withdrawal in wild-type and PR knockout mice. Neurosteroid withdrawal-induced α4-subunit upregulation was completely suppressed by antisense Egr3 inhibition. In the hippocampus kindling model of epilepsy, there was heightened seizure activity, significant reduction in the antiseizure sensitivity of diazepam (a benzodiazepine insensitive at α4βγ-receptors) and conferral of increased seizure protection of flumazenil (a low-affinity agonist at α4βγ-receptors) in neurosteroid-withdrawn wild-type and PR knockout mice. These observations are consistent with enhanced α4-containing receptor abundance in vivo. Neurosteroid withdrawal-induced seizure exacerbation, diazepam insensitivity, and flumazenil efficacy in the kindling model were reversed by inhibition of Egr3. These results indicate that neurosteroid withdrawal-induced upregulation of GABA-A receptor α4-subunit expression is mediated by the Egr3 via a PR-independent signaling pathway. These findings help advance our understanding of the molecular basis of

  19. Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes.

    Science.gov (United States)

    Daniel, A R; Gaviglio, A L; Knutson, T P; Ostrander, J H; D'Assoro, A B; Ravindranathan, P; Peng, Y; Raj, G V; Yee, D; Lange, C A

    2015-01-22

    Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

  20. Localization of estrogen receptor α and progesterone receptor B in bovine cervix and vagina during the follicular and luteal phases of the sexual cycle.

    Science.gov (United States)

    Sağsöz, H; Akbalik, M E; Saruhan, B G; Ketani, M A

    2011-08-01

    The localization and distribution of estrogen receptors (ERα) and progesterone receptors (PR-B) in the cervix and vagina of sexually mature bovines during the follicular and luteal phases of the sexual cycle were studied using immunohistochemistry. The estrous cycle stage of 23 Holstein bovines was assessed by gross and histological appearance of ovaries and blood steroid hormone values. Tissue samples from cervix and vagina were fixed in 10% formaldehyde for routine histological processing. Nuclear staining for ERα and PR-B was observed in the epithelial cells of the surface epithelium, stromal cells and smooth muscle cells. Generally, in the cervix, ERα immunoreactivity was more intense in the epithelial and smooth muscle cells during the follicular phase and in the epithelial cells during the luteal phase (p vagina, ERα and PR-B immunoreactivities were more intense in the epithelial cells than in the connective tissue cells and smooth muscle cells during the follicular and luteal phases (p vagina of bovines varied according to the cervical and vaginal cell types and the phases of the sexual cycle.

  1. The progesterone receptor antagonist, onapristone has differential effects on the timing and control of the luteolytic mechanism depending on timing of administration in sheep.

    Science.gov (United States)

    Mann, G E; Wathes, D C; Robinson, R S

    2013-08-25

    Cyclic ewes were treated with control vehicle or progesterone receptor antagonist (onapristone; 100mg i.m. twice daily) during either early (day 3-5) or late (day 12-14) luteal phase and plasma samples collected for hormone analysis and to determine endogenous and oxytocin induced PGF2α release. On day 14 and 17, ewes were euthanised and reproductive tracts collected for ovarian morphology and endometrium for oxytoxin and steroid hormone receptor analysis. Early treatment increased LH, but not progesterone or oestradiol, while late treatment elevated all three hormones. Early treatment delayed the up-regulation of endometrial oxytocin receptors and responsiveness to oxytocin challenge, delaying luteolysis. Late treatment advanced development of oxytocin receptors and responsiveness to oxytocin though not timing of luteolysis. Patterns of hormone receptor mRNA were differentially disrupted by treatments. Results provide mechanistic insight into hormonal control of the oestrous cycle and identify the ability of the luteolytic mechanism to dissociate from functional luteolysis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Progesterone modulates the proliferation and differentiation of human periodontal ligament cells.

    Science.gov (United States)

    Yuan, Gongjie; Cai, Chuan; Dai, Juan; Liu, Yali; Zhang, Rui; Dai, Yuanyuan; Wen, Li; Ding, Yin

    2010-08-01

    Hormone deficiency has been recognized as a risk factor for periodontal disease in postmenopausal women. However, the anabolic effects of progesterone on human periodontal ligament cells (hPDLCs) are still unclear. Therefore, the objective of this study was to detect the expression of progesterone receptor (PgR) in hPDLCs and investigate the bone-sparing effects of progesterone. We detected PgR expression in hPDLCs by reverse transcriptase-polymerase chain reaction and immunocytochemistry. After progesterone stimulation, the percentage of hPDLCs entering the S + G2M phase of the cell cycle increased significantly, accompanied by an increased cell growth curve. In both basic culture medium and osteogenic medium, progesterone activated alkaline phosphatase-positive cells and alizarin red-positive nodules. Moreover, mineralization-related markers were up-regulated by progesterone in both time-dependent and dose-dependent manners. In contrast, these effects of progesterone were blocked by the PgR antagonist (RU486). Our results demonstrated that the PgR is expressed in hPDLCs at the gene and protein level, and that progesterone can stimulate the proliferation and differentiation of the hPDLCs. These findings suggest that progesterone may play a significant role in osteoblastic function of hPDLCs and may influence the maintenance of alveolar bone mass.

  3. Influence of Dexamethasone on Some Reproductive Hormones and Uterine Progesterone Receptor Localization in Pregnant Yankasa Sheep in Semiarid Zones of Nigeria

    Directory of Open Access Journals (Sweden)

    Dauda Yahi

    2017-01-01

    Full Text Available Dexamethasone is widely used in both veterinary and human medical practices. However, it seems to cause some deleterious effects on pregnancy probably by causing changes in the reproductive hormone levels and their corresponding receptor concentrations. This study investigated the effects of dexamethasone on these parameters. Twenty healthy adult Yankasa sheep comprising 18 ewes and 2 rams were used for this study. Pregnancies were achieved by natural mating after estrus synchronization. Dexamethasone was administered at 0.25 mg/kg body weight on days 1, 3, and 5 during first trimester; days 51, 53, and 55 during second trimester; and days 101, 103, and 105 during the third trimester. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested through caesarean section for immunohistochemical analysis. Results showed that dexamethasone significantly (p0.05 effect on estrogen, while progesterone receptors (PR were upregulated. The abortion could probably be due to decreased progesterone concentrations as a consequence of the adverse effects on placenta. The PR upregulation may be a compensatory mechanism to increase progesterone sensitivity. It was concluded that dexamethasone should not be used in advanced pregnancy in Yankasa sheep.

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

    Directory of Open Access Journals (Sweden)

    Tarique N Hasan

    2011-03-01

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

  5. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype

    National Research Council Canada - National Science Library

    Abu‐Hayyeh, Shadi; Papacleovoulou, Georgia; Lövgren‐Sandblom, Anita; Tahir, Mehreen; Oduwole, Olayiwola; Jamaludin, Nurul Akmal; Ravat, Sabiha; Nikolova, Vanya; Chambers, Jenny; Selden, Clare; Rees, Myrddin; Marschall, Hanns‐Ulrich; Parker, Malcolm G; Williamson, Catherine

    2013-01-01

    ...)‐mediated bile acid homeostasis pathways. Here we report that the 3β‐sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients...

  6. Efficacy of endocrine therapy in relation to progesterone receptor and Ki67 expression in advanced breast cancer.

    Science.gov (United States)

    Rocca, Andrea; Farolfi, Alberto; Maltoni, Roberta; Carretta, Elisa; Melegari, Elisabetta; Ferrario, Cristiano; Cecconetto, Lorenzo; Sarti, Samanta; Schirone, Alessio; Fedeli, Anna; Andreis, Daniele; Pietri, Elisabetta; Ibrahim, Toni; Montalto, Erika; Amadori, Dino

    2015-07-01

    We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002-2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut-off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series (P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors (P = 0.026) or metastases (P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response.

  7. Immunohistochemical localization of 3β-Hydroxysteroid dehydrogenase and progesterone receptors in the ovary and placenta during gestation of the placentotrophic lizard Mabuya sp (Squamata: Scincidae).

    Science.gov (United States)

    Duarte-Méndez, Melissa; Quintero-Silva, Jennifer; Ramírez-Pinilla, Martha Patricia

    2018-02-27

    In squamates, progesterone (P) plays a key role in the inhibition of uterine mobility during egg retention in oviparous species, and during gestation in viviparous species. The corpus luteum (CL) is the main organ responsible for the production of P; however, in some species, the CL degenerates early and the P needed for gestation maintenance should be produced in other tissues. Mabuya sp (Scincidae) is a viviparous lizard with a prolonged gestation, it produces microlecithal eggs and, consequently, has an obligate placentotrophy related with a highly complex placenta. Its CL degenerates at early stages of gestation and therefore, other sources of P should exist. The aim of this study was to determine and localize by immunohistochemistry the production of P by detection of the enzyme 3β-Hydroxysteroid dehydrogenase (3β-HSD) and P receptors (PR) during gestation in the ovary and placenta of Mabuya sp. Positive and negative control sections were used. The ovary of this species localizes 3β-HSD and PR in the same tissues. The CL of the ovaries of females at early stages of gestation were positive for both molecules, whereas they did not localize from mid gestation to the end of pregnancy. Previtellogenic and vitellogenic follicles labelled for both molecules in the follicular epithelium and thecae. The placenta of Mabuya sp. demonstrated the potential for P production from mid gestation to the end of gestation in the uterine and chorionic tissues. PR were located in the uterine tissues throughout gestation, with a decrease towards its completion. Western blot analysis confirmed the presence of 3β-HSD mainly in the ovary of early pregnant females and in the placental tissues at mid gestation stages. Therefore, the chorioallantoic placenta of Mabuya sp. has an endocrine function producing the P needed for gestation and replacing the CL from mid gestation to the end of pregnancy. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Progestogen levels, Progesterone Receptor Gene polymorphisms, and mammographic density changes: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study (PEPI-MDS)

    Science.gov (United States)

    Lee, Eunjung; Ingles, Sue A.; Van Den Berg, David; Wang, Wei; LaVallee, Chris; Huang, Mei-Hua; Crandall, Carolyn J.; Stanczyk, Frank Z.; Greendale, Gail A.; Ursin, Giske

    2015-01-01

    Objective Estrogen plus progestin therapy (EPT) in postmenopausal women increases breast cancer risk and mammographic density to a higher extent than does estrogen therapy (ET) alone. Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestin Interventions (PEPI) trial showed that EPT-induced increases in serum estrone and estrone sulfate levels were positively correlated with increases in mammographic density. Here, after adjusting for serum estrone and estrone sulfate levels, we investigated the roles of post-treatment serum progestogen increase and of progesterone receptor gene (PGR) genetic variations on changes in mammographic density. Methods We measured percent mammographic density and serum progestogen levels in 280 PEPI participants randomized to EPT treatment. Analyses of genetic variations in PGR were limited to 260 white women for whom we successfully obtained PGR genotypes. We used linear regression analyses to determine how increase in progestogen levels and PGR genetic variations influenced mammographic density change following EPT. Results The increase in post-treatment serum progestogen level was positively associated with greater increases in mammographic density after adjustment for covariates (P-trend=0.044). Compared to women in the lowest quartile of serum progestogen, women in the highest quartile experienced a 3.5% greater increase in mammographic density (P=0.046). We did not find a strong indication that genetic variations in PGR were associated with mammographic density increase, or modified the association with serum progestogen, however confidence in these null findings is constrained by our small sample size. Conclusions Our results suggest that higher serum progestogen levels resulting from EPT treatment lead to greater increases in mammographic density. PMID:22105149

  9. Quantitative analysis of expression level of estrogen and progesterone receptors and VEGF genes in human endometrial stromal cells after treatment with nicotine.

    Science.gov (United States)

    Totonchi, Hamidreza; Miladpour, Behnoosh; Mostafavi-Pour, Zohreh; Khademi, Fatemeh; Kasraeian, Maryam; Zal, Fatemeh

    2016-10-01

    Cigarette smoke is a complex mixture of toxic chemicals, including nicotine, carbon monoxide, and several recognized carcinogens and mutagens. Nicotine has a direct disturbing influence on steroid hormones (estrogen and progesterone), which are essential components of the female reproductive system, but the effect of nicotine on the hormone receptors is not yet clear. The aim of this study was to elucidate the effect of nicotine on the expression of estrogen receptor (ER), progesterone receptor (PR), and vascular endothelial growth factor (VEGF) in endometrial stromal cells. Expression levels of PR, ER, and VEGF in human endometrial stromal primary cells treated with nicotine (0, 10 -11 , 10 -8 , and 10 -6  μM) for 24 h were measured by quantitative real-time PCR. MTT assay demonstrated that nicotine decreased cell viability in a dose-dependent manner. Real-time PCR data showed that despite decrease in ER expression in the nicotine-treated groups compared with the control, nicotine exerted an increased inhibitory effect on PR expression compared to that on ER expression. VEGF mRNA expression in nicotine-treated endometrial stromal cells was increased. The results from this study provide novel evidence for inhibitory effects of nicotine on steroid hormones receptor expression in human primary endometrial cells. Also, our data suggest that nicotine might have angiogenesis effects on these cells.

  10. Progesterone increases dopamine neurone number in differentiating mouse embryonic stem cells.

    Science.gov (United States)

    Díaz, N F; Díaz-Martínez, N E; Velasco, I; Camacho-Arroyo, I

    2009-08-01

    Progesterone participates in the regulation of several functions in mammals, including brain differentiation and dopaminergic transmission, but the role of progesterone in dopaminergic cell differentiation is unknown. We investigated the effects of progesterone on dopaminergic differentiation of embryonic stem cells using a five-stage protocol. Cells were incubated with different progesterone concentrations during the proliferation (stage 4) or differentiation (stage 5) phases. Progesterone added at 1, 10 and 100 nm during stage 4 increased the number of dopamine neurones at stage 5 by 72%, 80% and 62%, respectively, compared to the control group. The administration of progesterone at stage 5 did not induce significant changes in the number of dopamine neurones. These actions were not mediated by the activation of intracellular progesterone receptors because RU 486 did not block the positive effects of progesterone on differentiation to dopaminergic neurones. The results obtained suggest that progesterone should prove useful with respect to producing higher proportions of dopamine neurones from embryonic stem cells in the treatment of Parkinson's disease.

  11. The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth.

    Science.gov (United States)

    Bustos, Martha L; Caritis, Steve N; Jablonski, Kathleen A; Reddy, Uma M; Sorokin, Yoram; Manuck, Tracy; Varner, Michael W; Wapner, Ronald J; Iams, Jay D; Carpenter, Marshall W; Peaceman, Alan M; Mercer, Brian M; Sciscione, Anthony; Rouse, Dwight J; Ramin, Susan M

    2017-09-01

    Infants born preterm birth are the leading cause of mortality in children preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes. We sought to: (1) determine the relation between 17-alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs

  12. Effect of a Selective Progesterone Receptor Modulator on Induction of Apoptosis in Uterine Fibroids In Vivo

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    Petr Horak

    2012-01-01

    Full Text Available Aim. To determine if hormonal treatment induces apoptosis in uterine fibroids. Methods. Immunohistochemical examination of fibroid tissue, using avidin-biotin complex and cleaved caspase-3 antibody for detecting apoptosis, was performed in premenopausal women who underwent 12-week treatment with oral SPRM (6 patients with 5 mg and 5 patients with 10 mg of ulipristal acetate per day or gonadoliberin agonist (GnRHa, 17 patients and subsequent myomectomy or hysterectomy for symptomatic uterine fibroids. Ten patients with no presurgical hormonal treatment were used as controls. Results. Apoptosis was present in a significantly higher proportion of patients treated with ulipristal acetate compared to GnRHa (P=0.01 and to patients with no hormonal treatment (P=0.01. In contrast to an AI of 158.9 in SPRM patients, the mean AI was 27.5 and 2.0 in GnRHa and control groups, respectively. No statistical difference in the AI was observed between the two groups of patients treated with ulipristal acetate (5 mg or 10 mg. Conclusion. Treatment with ulipristal acetate induces apoptosis in uterine fibroid cells. This effect of SPRM may contribute to their positive clinical effect on uterine fibroids.

  13. The prognostic value of age for invasive lobular breast cancer depending on estrogen receptor and progesterone receptor-defined subtypes: A NCDB analysis.

    Science.gov (United States)

    Liu, Jieqiong; Chen, Kai; Mao, Kai; Su, Fengxi; Liu, Qiang; Jacobs, Lisa K

    2016-02-02

    We aimed to assess the effect of age on survival according to estrogen receptor (ER) and progesterone receptor (PR)-defined lobular breast cancer subtype in a wide age range. 43,230 invasive lobular breast cancer women without comorbidities diagnosed between 2004 and 2011 in the National Cancer Database (NCDB) were analyzed. The effects of age on overall survival (OS) among different age groups were evaluated by log-rank test and Cox proportional model. Multivariate analysis showed that patients diagnosed at both young (ages had worse prognosis compared with those in the middle ages. We further analyzed the interaction between age and molecular subtype for predicting OS: in ER+PR+ subtype, the HR of OS declined with age from 1.55 (95% CI, 1.08-2.22; P = 0.019) in the group younger than 35 years to 1.38 (1.02-1.86; P = 0.036) in the 35-39 group, but increased with age to 10.1 (8.49-11.94; P 0.1); and in ER-PR+ subgroup, the HRs were similar in patients younger than 70 (P > 0.1); thus, the plots of HRs in these three subtypes remained steady until the age of 60 or 70. Our findings identified that the effect of age on OS in lobular breast cancer varied with ER/PR-defined subtypes. Personalized treatment strategies should be developed to improve outcomes of breast cancer patients with different ages and ER/PR statuses.

  14. α-Estrogen and Progesterone Receptors Modulate Kisspeptin Effects on Prolactin: Role in Estradiol-Induced Prolactin Surge in Female Rats.

    Science.gov (United States)

    Aquino, Nayara S S; Araujo-Lopes, Roberta; Henriques, Patricia C; Lopes, Felipe E F; Gusmao, Daniela O; Coimbra, Candido C; Franci, Celso R; Reis, Adelina M; Szawka, Raphael E

    2017-06-01

    Kisspeptin (Kp) regulates prolactin (PRL) in an estradiol-dependent manner. We investigated the interaction between ovarian steroid receptors and Kp in the control of PRL secretion. Intracerebroventricular injections of Kp-10 or Kp-234 were performed in ovariectomized (OVX) rats under different hormonal treatments. Kp-10 increased PRL release and decreased 3,4-dihydroxyphenylacetic acid levels in the median eminence (ME) of OVX rats treated with estradiol (OVX+E), which was prevented by tamoxifen. Whereas these effects of Kp-10 were absent in OVX rats, they were replicated in OVX rats treated with selective agonist of estrogen receptor (ER)α, propylpyrazole triol, but not of ERβ, diarylpropionitrile. Furthermore, the Kp-10-induced increase in PRL was two times higher in OVX+E rats also treated with progesterone (OVX+EP), which was associated with a reduced expression of both tyrosine hydroxylase (TH) and Ser40-phosphorylated TH in the ME. Kp-10 also reduced dopamine levels in the ME of OVX+EP rats, an effect blocked by the progesterone receptor (PR) antagonist RU486. We also determined the effect of Kp antagonism with Kp-234 on the estradiol-induced surges of PRL and luteinizing hormone (LH), using tail-tip blood sampling combined with ultrasensitive enzyme-linked immunosorbent assay. Kp-234 impaired the early phase of the PRL surge and prevented the LH surge in OVX+E rats. Thus, we provide evidence that Kp stimulation of PRL release requires ERα and is potentiated by progesterone via PR activation. Moreover, alongside its essential role in the LH surge, Kp seems to play a role in the peak phase of the estradiol-induced PRL surge. Copyright © 2017 Endocrine Society.

  15. Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection

    DEFF Research Database (Denmark)

    Tramm, Trine; Hennig, Guido; Kyndi, Marianne

    2013-01-01

    Gene expression analysis on messenger RNA (mRNA) purified from formalin-fixed, paraffin-embedded tissue is increasingly used for research purposes. Tissue heterogeneity may question specificity and interpretation of results from mRNA isolated from a whole slide section, and thresholds for minimal...... tumor content in the paraffin block or macrodissection are used to avoid contamination from non-neoplastic tissue. The aim was to test if mRNA from tissue surrounding breast cancer affected quantification of estrogen receptor α (ESR1), progesterone receptor (PGR) and human epidermal growth factor...... receptor 2 (ERBB2), by comparing gene expression from whole slide and tumor-enriched sections, and correlating gene expression from whole slide sections with corresponding immunohistochemistry. Gene expression, based on mRNA extracted from a training set (36 paraffin blocks) and two validation sets (133...

  16. Expression of progesterone receptor membrane component-2 within the immature rat ovary and its role in regulating mitosis and apoptosis of spontaneously immortalized granulosa cells.

    Science.gov (United States)

    Griffin, Daniel; Liu, Xiufang; Pru, Cindy; Pru, James K; Peluso, John J

    2014-08-01

    Progesterone receptor membrane component 2 (Pgrmc2) mRNA was detected in the immature rat ovary. By 48 h after eCG, Pgrmc2 mRNA levels decreased by 40% and were maintained at 48 h post-hCG. Immunohistochemical studies detected PGRMC2 in oocytes and ovarian surface epithelial, interstitial, thecal, granulosa, and luteal cells. PGRMC2 was also present in spontaneously immortalized granulosa cells, localizing to the cytoplasm of interphase cells and apparently to the mitotic spindle of cells in metaphase. Interestingly, PGRMC2 levels appeared to decrease during the G1 stage of the cell cycle. Moreover, overexpression of PGRMC2 suppressed entry into the cell cycle, possibly by binding the p58 form of cyclin dependent kinase 11b. Conversely, Pgrmc2 small interfering RNA (siRNA) treatment increased the percentage of cells in G1 and M stage but did not increase the number of cells, which was likely due to an increase in apoptosis. Depleting PGRMC2 did not inhibit cellular (3)H-progesterone binding, but attenuated the ability of progesterone to suppress mitosis and apoptosis. Taken together these studies suggest that PGRMC2 affects granulosa cell mitosis by acting at two specific stages of the cell cycle. First, PGRMC2 regulates the progression from the G0 into the G1 stage of the cell cycle. Second, PGRMC2 appears to localize to the mitotic spindle, where it likely promotes the final stages of mitosis. Finally, siRNA knockdown studies indicate that PGRMC2 is required for progesterone to slow the rate of granulosa cell mitosis and apoptosis. These findings support a role for PGRMC2 in ovarian follicle development. © 2014 by the Society for the Study of Reproduction, Inc.

  17. Targeted Radiotherapy of Estrogen Receptor Positive Tumors

    Energy Technology Data Exchange (ETDEWEB)

    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.

  18. Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: dependence on GABA(A) receptor alpha4 subunit upregulation.

    Science.gov (United States)

    Hsu, Fu-Chun; Smith, Sheryl S

    2003-01-01

    Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alphaTHP). This 3alpha,5alpha-THP withdrawal also results in a decreased decay time constant for GABA-gated current assessed using whole cell patch-clamp techniques on pyramidal cells acutely dissociated from CA1 hippocampus. The purpose of this study was to test the hypothesis that the decreases in total integrated GABA-gated current observed at the level of the isolated pyramidal cell would be manifested as a reduced GABA inhibition at the circuit level following hormone withdrawal. Toward this end, adult, female rats were administered P via subcutaneous capsule for 3 wk using a multiple withdrawal paradigm. We then evaluated paired-pulse inhibition (PPI) of pyramidal neurons in CA1 hippocampus using extracellular recording techniques in hippocampal slices from rats 24 h after removal of the capsule (P withdrawal, P Wd). The population spike (PS) was recorded at the stratum pyramidale following homosynaptic orthodromic stimulation in the nearby stratum radiatum. The threshold for eliciting a response was decreased after P Wd, and the mean PS amplitude was significantly increased compared with control values at this time. Paired pulses with 10-ms inter-pulse intervals were then applied across an intensity range from 2 to 20 times threshold. Evaluation of paired-pulse responses showed a significant 40-50% reduction in PPI for PS recorded in the hippocampal CA1 region after P Wd, suggesting an increase in circuit excitability. At this time, enhancement of PPI by the benzodiazepine lorazepam (LZM; 10 microM) was prevented, while pentobarbital (10 microM) potentiation of PPI was comparable to control levels of response. These data are consistent with upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) as we have previously

  19. Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABAA Receptor α4 Subunit Upregulation

    Science.gov (United States)

    Hsu, Fu-Chun; Smith, Sheryl S.

    2010-01-01

    Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3α-OH-5α-pregnan-20-one (3α,5α-THP). This 3α,5α-THP withdrawal also results in a decreased decay time constant for GABA-gated current assessed using whole cell patch-clamp techniques on pyramidal cells acutely dissociated from CA1 hippocampus. The purpose of this study was to test the hypothesis that the decreases in total integrated GABA-gated current observed at the level of the isolated pyramidal cell would be manifested as a reduced GABA inhibition at the circuit level following hormone withdrawal. Toward this end, adult, female rats were administered P via subcutaneous capsule for 3 wk using a multiple withdrawal paradigm. We then evaluated paired-pulse inhibition (PPI) of pyramidal neurons in CA1 hippocampus using extracellular recording techniques in hippocampal slices from rats 24 h after removal of the capsule (P withdrawal, P Wd). The population spike (PS) was recorded at the stratum pyramidale following homosynaptic orthodromic stimulation in the nearby stratum radiatum. The threshold for eliciting a response was decreased after P Wd, and the mean PS amplitude was significantly increased compared with control values at this time. Paired pulses with 10-ms inter-pulse intervals were then applied across an intensity range from 2 to 20 times threshold. Evaluation of paired-pulse responses showed a significant 40–50% reduction in PPI for PS recorded in the hippocampal CA1 region after P Wd, suggesting an increase in circuit excitability. At this time, enhancement of PPI by the benzodiazepine lorazepam (LZM; 10 µM) was prevented, while pentobarbital (10 µM) potentiation of PPI was comparable to control levels of response. These data are consistent with upregulation of the α4 subunit of the GABAA receptor (GABAR) as we have previously shown. Moreover, the

  20. Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABAA Receptor α4 Subunit Upregulation

    National Research Council Canada - National Science Library

    Fu-Chun Hsu; Sheryl S. Smith

    2003-01-01

    Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3α-OH-5α-pregnan-20-one (3α,5αTHP). This 3α,5α...

  1. Synthesis of the 7alpha-cyano-(17alpha,20E/Z)-[125I]iodovinyl-19-nortestosterones: potential radioligands for androgen and progesterone receptors.

    Science.gov (United States)

    Ali, Hasrat; Rousseau, Jacques; Ahmed, Naseem; Guertin, Veronique; Hochberg, Richard B; van Lier, Johan E

    2003-12-01

    We report the preparation of the 7alpha-cyano derivative of the isomeric (17alpha,20E/Z)-[125I]iodovinyl-19-nortestosterones (IVNT) together with their binding affinity for the androgen receptor (AR) and their biodistribution in two different animal models. The cyano group was introduced at the 7alpha-position by hydrocyanation of 4,6-estradien-17beta-ol-3-one with diethylaluminum cyanide. Selective protection of the A-ring enone system as the dienol ether followed by ethynylation and deprotection under base and acid hydrolysis condition gave 7alpha-cyano-17alpha-ethynyl-19-nortestosterone. The stannyl derivatives were prepared by addition of tri-n-butylstannyl hydride and converted stereospecifically to the corresponding [125I]iodovinyl analog using [125I]NaI and H2O2. The [125I]iodovinylsteroids were intravenously administered to male rats and estrogen-primed immature female rats and tissue uptake was measured up to 6h post-injection. Co-administration of NLP-004 or ORG-2058, highly selective ligands for the progesterone receptor, to the female rats did not affect uterus uptake of the 125I-ligands. However co-injection of testosterone to DES-primed male rats induced a marked increase in prostate uptake of the 20Z-isomer of 7alpha-cyano-[125I]-IVNT. The relative binding affinity (RBA) of either 7alpha-cyano-(17alpha,20E/Z)-IVNT isomer for the AR is low (RBA=4 and 3, respectively, versus 100 for 5alpha-dihydrotestosterone (DHT)), suggesting the absence of a possible role of the AR in the localization process. These findings contrast previously reported data for the analogous 7alpha-methyl-[125I]-IVNT where co-administration of testosterone was shown to result in a 50% drop in prostate uptake. These data indicate that the addition of an electron withdrawing 7alpha-cyano group to 123I-labeled nortestosterone derivatives does not improve their potential to serve as SPECT agents for the imaging of AR densities in the prostate.

  2. A stable human progesterone receptor expressing HeLa reporter cell line as a tool in chemical evaluation at the different cell-cycle phases.

    Science.gov (United States)

    Mori, Tetsushi; Murata, Mai; Yoshino, Tomoko; Nakasono, Satoshi; Saito, Fumiyo; Takeyama, Haruko; Matsunaga, Tadashi

    2009-04-25

    Specific molecular events, characteristic of each cell-cycle phase may have direct effect to the functionality of nuclear receptors. Based on this understanding, the evaluation of lipophilic chemicals at the different cell-cycle phases is significant and should be considered. In order to achieve the aim of performing large-scale dose-response analysis on the effects of lipophilic chemicals at the different cell-cycle phases, a stable, sensitive and highly selective human progesterone receptor (hPR) expressing HeLa reporter cell line, hPRLuc-20, was established. Upon the establishment of the hPRLuc-20 cells, they were synchronized to the G(1), S and G(2) phases and treated with progesterone (PROG) and promegestone (R5020). The cells successfully showed that at the different cell-cycle phase, both agonists resulted in different cellular responses. The differences in response supports that hPR expressed within the hPRLuc-20 cells do respond in a cell-cycle dependent manner, thus showing the cells' compatibility in large-scale dose-response analyses of chemicals. It is hopeful that the advanced application of the hPRLuc-20 cells could contribute to provide fundamental hints to further understand the function of hPR, and provide key observations to elucidate the nature of these chemicals with hPR, its corresponding co-regulators and transcription factors.

  3. Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection

    DEFF Research Database (Denmark)

    Tramm, Trine; Hennig, Guido; Kyndi, Marianne

    2013-01-01

    Gene expression analysis on messenger RNA (mRNA) purified from formalin-fixed, paraffin-embedded tissue is increasingly used for research purposes. Tissue heterogeneity may question specificity and interpretation of results from mRNA isolated from a whole slide section, and thresholds for minimal...... tumor content in the paraffin block or macrodissection are used to avoid contamination from non-neoplastic tissue. The aim was to test if mRNA from tissue surrounding breast cancer affected quantification of estrogen receptor α (ESR1), progesterone receptor (PGR) and human epidermal growth factor...... and ERBB2, and 83 % for PGR. Overall agreements, when comparing mRNA expression to immunohistochemistry, were 100 % (ERBB2), 89 % (ESR1) and 83 % (PGR), which was confirmed in the validation sets. Percentage of tumor in the sections did not influence the results. In conclusion, reliable quantification...

  4. Down-regulation of progesterone receptor membrane component 1 (PGRMC1 in peripheral nucleated blood cells associated with premature ovarian failure (POF and polycystic ovary syndrome (PCOS

    Directory of Open Access Journals (Sweden)

    Karlström Per-Olof

    2010-06-01

    Full Text Available Abstract Background Progesterone receptor membrane component 1 (PGRMC1 is a member of a progesterone-binding complex implicated in female reproduction. We aimed i to determine the natural expression of PGRMC1 in peripheral nucleated blood cells throughout the menstrual cycle and ii to investigate any association between PGRMC1 levels in leukocytes and conditions characterized by reduced fertility. Methods We analyzed PGRMC1 expression in peripheral leukocytes from 15 healthy cycling women over four weeks. Additionally, we determined PGRMC1 levels in samples from patients with premature ovarian failure (POF and polycystic ovary syndrome (PCOS as well as in healthy postmenopausal women and male controls. The levels of PGRMC1 protein in nucleated peripheral blood cells were quantified by Western blot analysis. Results PGRMC1 levels did not vary significantly throughout the menstrual cycle. We observed a significant down-regulation of PGRMC1 in postmenopausal women and in patients with premature ovarian failure (POF and polycystic ovary syndrome (PCOS when compared to early follicular phase of healthy women. Conclusion This study suggests that reduced levels of PGRMC1 in peripheral leukocytes are associated with perturbed ovulatory function.

  5. Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABAA Receptor α4 Subunit Upregulation

    OpenAIRE

    Hsu, Fu-Chun; Smith, Sheryl S.

    2003-01-01

    Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3α-OH-5α-pregnan-20-one (3α,5α-THP). This 3α,5α-THP withdrawal also results in a decreased decay time constant for GABA-gated current assessed using whole cell patch-clamp techniques on pyramidal cells acutely dissociated from CA1 hippocampus. The purpose of this study was to test the hypothesis that the...

  6. Polimorfismo do gene dos receptores de progesterona e o aborto espontâneo de repetição Progesterone receptor gene polymorphism and recurrent spontaneous abortion

    Directory of Open Access Journals (Sweden)

    Évelyn Traina

    2010-05-01

    Full Text Available OBJETIVO: investigar se polimorfismos dos genes que codificam o receptor de progesterona (PROGINS estão relacionados à ocorrência de aborto espontâneo de repetição (AER. MÉTODOS: em estudo caso-controle, foram selecionados 85 pacientes com antecedente de pelo menos três abortos precoces sem etiologia definida (Grupo Caso e 157 mulheres com história de pelo menos duas gestações de termo sem intercorrências e sem passado de abortamento (Grupo Controle. Realizada coleta de 10 mL de sangue por punção venosa periférica e extração de DNA pela técnica DTAB/CTAB. As genotipagens foram feitas por reação em cadeia de polimerase (PCR, nas condições de ciclagem específica para o polimorfismo em estudo, seguida de amplificação em gel de agarose a 2%. A visualização das bandas foi feita sob luz ultravioleta e os géis foram fotografados. As diferenças genotípicas e alélicas entre os dois grupos para o polimorfismo PROGINS foram calculadas pelo teste de χ2, adotando-se como nível de significância valores de pPURPOSE: to assess a possible association between polymorphism of the progesterone receptor gene (PROGINS and recurrent spontaneous abortion (RSA. METHODS: in this case-control study, 85 women with at least three previous spontaneous abortions without an identifiable cause (RSA Group and 157 women with at least two previous term pregnancies without pathologies and no previous miscarriage (Control Group were selected. An amount of 10 mL of peripheral blood was collected by venipuncture and genomic DNA was extracted by the DTAB/CTAB method, followed by the polymerase chain reaction (PCR under specific conditions for this polymorphism and by amplification by 2% agarose gel electrophoresis. The bands were visualized with an ultraviolet light transilluminator and the gels were photographed. Differences in the PROGINS genotype and allele frequencies between groups were analyzed by the χ2 test, with the level of significance set

  7. Pesquisa de estrógeno e progesterona no epitélio das pregas vocais de mulheres por imunohistoquímica Immunohistochemical searching for estrogen and progesterone receptors in women vocal fold epithelia

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    Oswaldo Angel Bellido Rios

    2008-08-01

    Full Text Available A laringe é extremamente sensível a mudanças endocrinológicas. A maioria das alterações da mucosa das pregas vocais é causada por modificações do conteúdo líquido das pregas vocais e das suas modificações epiteliais. O estrógeno e a progesterona interferem e modificam esse conteúdo líquido das pregas vocais. O objetivo deste trabalho é verificar a presença de receptores de estrógeno e progesterona no epitélio das pregas vocais de mulheres. MATERIAL E MÉTODO: Estudo de casos prospectivos. Foram realizados exames de imunohistoquímica para receptores de estrógeno e progesterona em 19 espécimes de epitélio de pregas vocais que não apresentavam quaisquer indícios de afecção, inclusive inflamatória. Foram descartados casos de pacientes com idade superior a 40 anos e inferior a 15 anos. RESULTADOS: Foram encontrados receptores para progesterona em 18 de 19 pacientes. Os receptores de progesterona estão localizados tanto no núcleo quanto no citoplasma e principalmente na camada basal. Não houve nenhum caso de receptores de estrógeno nas pregas vocais. CONCLUSÃO: O epitélio das pregas vocais apresenta receptores para progesterona, tanto no citoplasma quanto no núcleo. Não foram encontrados receptores para estrógeno no epitélio das pregas vocais estudadas.Larynx is extremely sensitive to endocrinologic changes. Most vocal fold mucosa alterations are caused by changes in vocal fold liquid content and its epithelial changes. Estrogen and progesterone interfere and change this liquid content in the vocal folds. Our goal with the present paper is to study the presence of estrogen and progesterone receptors on vocal fold epithelium in 19 vocal fold epithelium specimens that did not present any indication of disease, especially inflammatory disease. We discarded those cases of patients above 40 years of age and those below 15. RESULTS: we found progesterone receptors in 18 of the 19 patients. The progesterone receptors

  8. ck2-Dependent Phosphorylation of Progesterone Receptors (PR) on Ser81 Regulates PR-B Isoform-Specific Target Gene Expression in Breast Cancer Cells ▿

    Science.gov (United States)

    Hagan, Christy R.; Regan, Tarah M.; Dressing, Gwen E.; Lange, Carol A.

    2011-01-01

    Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G1/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments. PMID:21518957

  9. The dialectic role of progesterone.

    Science.gov (United States)

    Huber, Johannes C; Ott, Johannes

    2009-04-20

    Progesterone is known to be metabolized into various metabolites exerting various effects, predominantly into 5alpha-pregnanes and 4-pregnenes. Studies on uterine tissues showed numerous progesterone-converting enzymes such as 5alpha-reductase (5alphaR), 5beta-reductase, 3alpha-, 3beta-, 20alpha-, and 20beta-hydroxysteroid oxidoreductases and others. The main progesterone-metabolizing enzymes in human breast tissues are 5alphaR, 3alpha-HSO 3beta-HSO, and 20alpha-HSO. Tumor genesis in the breast has been shown to be enhanced by high 5alphaR activity and suppression of 3alpha-HSO and 20alpha-HSO. A major determinant of 5alphaR, the breast's gate-keeping enzyme activity is the genetic variation in the enzyme's gene. Two polymorphisms within the steroid 5alphaR type 2 gene, Ala>Thr at codon 49 and Val>Leu at codon 89 have been reported to strongly affect the enzyme's activity, even in regard to breast cancer risk. As steroid hormones are known to be converted into many other steroids occupying different receptors and thereby exerting various different effects, progesterone receptors are important factors when mediating the hormone's effects. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into PR-B, a potent transcriptional activator, and PR-A, the shorter isoform, necessary to oppose the effects of PR-B. In addition, endocrine reactions are modulated by epigenetics. The expression of progesterone receptors has been shown to be up- and downregulated by various epigenetic mechanisms. Many factors must be also taken into account in hormonal (replacement) therapy. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists.

  10. 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

  11. Identification of a phosphorylation site in the hinge region of the human progesterone receptor and additional amino-terminal phosphorylation sites.

    Science.gov (United States)

    Knotts, T A; Orkiszewski, R S; Cook, R G; Edwards, D P; Weigel, N L

    2001-03-16

    We have previously reported the identification of seven in vivo phosphorylation sites in the amino-terminal region of the human progesterone receptor (PR). From our previous in vivo studies, it was evident that several phosphopeptides remained unidentified. In particular, we wished to determine whether human PR contains a phosphorylation site in the hinge region, as do other steroid receptors including chicken PR, human androgen receptor, and mouse estrogen receptor. Previously, problematic trypsin cleavage sites hampered our ability to detect phosphorylation sites in large incomplete tryptic peptides. Using a combination of mass spectrometry and in vitro phosphorylation, we have identified six previously unidentified phosphorylation sites in human PR. Using nanoelectrospray ionization mass spectrometry, we have identified two new in vivo phosphorylation sites, Ser(20) and Ser(676), in baculovirus-expressed human PR. Ser(676) is analogous to the hinge site identified in other steroid receptors. Additionally, precursor ion scans identified another phosphopeptide that contains Ser(130)-Pro(131), a likely candidate for phosphorylation. In vitro phosphorylation of PR with Cdk2 has revealed five additional in vitro Cdk2 phosphorylation sites: Ser(25), Ser(213), Thr(430), Ser(554), and Ser(676). At least two of these, Ser(213) and Ser(676), are authentic in vivo sites. We confirmed the presence of the Cdk2-phosphorylated peptide containing Ser(213) in PR from in vivo labeled T47D cells, indicating that this is an in vivo site. Our combined studies indicate that most, if not all, of the Ser-Pro motifs in human PR are sites for phosphorylation. Taken together, these data indicate that the phosphorylation of PR is highly complex, with at least 14 phosphorylation sites.

  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.

    Science.gov (United States)

    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. Progesterone receptor-mediated regulation of N-acetylneuraminate pyruvate lyase (NPL in mouse uterine luminal epithelium and nonessential role of NPL in uterine function.

    Directory of Open Access Journals (Sweden)

    Shuo Xiao

    Full Text Available N-acetylneuraminate pyruvate lyase (NPL catalyzes N-acetylneuraminic acid, the predominant sialic acid. Microarray analysis of the periimplantation mouse uterine luminal epithelium (LE revealed Npl being the most downregulated (35× gene in the LE upon embryo implantation. In natural pregnant mouse uterus, Npl expression increased 56× from gestation day 0.5 (D0.5 to D2.5. In ovariectomized mouse uterus, Npl was significantly upregulated by progesterone (P4 but downregulated by 17β-estradiol (E2. Progesterone receptor (PR antagonist RU486 blocked the upregulation of Npl in both preimplantation uterus and P4-treated ovariectomized uterus. Npl was specifically localized in the preimplantation D2.5 and D3.5 uterine LE. Since LE is essential for establishing uterine receptivity, it was hypothesized that NPL might play a critical role in uterine function, especially during embryo implantation. This hypothesis was tested in the Npl ((-/- mice. No significant differences were observed in the numbers of implantation sites on D4.5, gestation periods, litter sizes, and postnatal offspring growth between wild type (WT and Npl ((-/- females from mating with WT males. Npl ((-/-xNpl ((-/- crosses produced comparable little sizes as that from WTxWT crosses. Comparable mRNA expression levels of several genes involved in sialic acid metabolism were observed in D3.5 uterus and uterine LE between WT and Npl ((-/-, indicating no compensatory upregulation in the D3.5 Npl ((-/- uterus and LE. This study demonstrates PR-mediated dynamic expression of Npl in the periimplantation uterus and dispensable role of Npl in uterine function and embryo development.

  14. Correlation of breast cancer subtypes, based on estrogen receptor, progesterone receptor, and HER2, with functional imaging parameters from {sup 68}Ga-RGD PET/CT and {sup 18}F-FDG PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hai-Jeon [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University College of Medicine, The Institute of Radiation Medicine, Seoul (Korea, Republic of); Ewha Womans University School of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kang, Keon Wook; Jeong, Jae Min; Chung, June-Key [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Biomedical Sciences, Seoul (Korea, Republic of); Seoul National University College of Medicine, The Institute of Radiation Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Chun, In Kook [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kangwon National University Hospital, Department of Nuclear Medicine, Chuncheon, Kangwon-Do (Korea, Republic of); Cho, Nariya [Seoul National University College of Medicine, Department of Radiology, Jongno-gu, Seoul (Korea, Republic of); Im, Seock-Ah [Seoul National University College of Medicine, Department of Internal Medicine, Seoul (Korea, Republic of); Jeong, Sunjoo [Dankook University, Department of Molecular Biology, Yongin (Korea, Republic of); Lee, Song [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University College of Medicine, The Institute of Radiation Medicine, Seoul (Korea, Republic of); Jung, Kyeong Cheon [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Lee, Yun-Sang [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of); Lee, Dong Soo [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University College of Medicine, The Institute of Radiation Medicine, Seoul (Korea, Republic of); Seoul National University, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul (Korea, Republic of); Moon, Woo Kyung [Seoul National University College of Medicine, Department of Radiology, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Biomedical Sciences, Seoul (Korea, Republic of); Seoul National University College of Medicine, The Institute of Radiation Medicine, Seoul (Korea, Republic of)

    2014-08-15

    Imaging biomarkers from functional imaging modalities were assessed as potential surrogate markers of disease status. Specifically, in this prospective study, we investigated the relationships between functional imaging parameters and histological prognostic factors and breast cancer subtypes. In total, 43 patients with large or locally advanced invasive ductal carcinoma (IDC) were analyzed (47.6 ± 7.5 years old). {sup 68}Ga-Labeled arginine-glycine-aspartic acid (RGD) and {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) were performed. The maximum and average standardized uptake values (SUV{sub max} and SUV{sub avg}) from RGD PET/CT and SUV{sub max} and SUV{sub avg} from FDG PET/CT were the imaging parameters used. For histological prognostic factors, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression was identified using immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Four breast cancer subtypes, based on ER/PR and HER2 expression (ER/PR+,Her2-, ER/PR+,Her2+, ER/PR-,Her2+, and ER/PR-,Her2-), were considered. Quantitative FDG PET parameters were significantly higher in the ER-negative group (15.88 ± 8.73 vs 10.48 ± 6.01, p = 0.02 for SUV{sub max}; 9.40 ± 5.19 vs 5.92 ± 4.09, p = 0.02 for SUV{sub avg}) and the PR-negative group (8.37 ± 4.94 vs 4.79 ± 3.93, p = 0.03 for SUV{sub avg}). Quantitative RGD PET parameters were significantly higher in the HER2-positive group (2.42 ± 0.59 vs 2.90 ± 0.75, p = 0.04 for SUV{sub max}; 1.60 ± 0.38 vs 1.95 ± 0.53, p = 0.04 for SUV{sub avg}) and showed a significant positive correlation with the HER2/CEP17 ratio (r = 0.38, p = 0.03 for SUV{sub max} and r = 0.46, p < 0.01 for SUV{sub avg}). FDG PET parameters showed significantly higher values in the ER/PR-,Her2- subgroup versus the ER/PR+,Her2- or ER/PR+,Her2+ subgroups, while RGD PET parameters showed significantly lower values in the ER

  15. Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring.

    Science.gov (United States)

    Takagi, Hironori; Shibutani, Makoto; Lee, Kyoung-Youl; Masutomi, Naoya; Fujita, Haruka; Inoue, Kaoru; Mitsumori, Kunitoshi; Hirose, Masao

    2005-10-15

    We have previously examined the impact of perinatal exposure to ethinylestradiol (EE), methoxychlor (MXC), diisononyl phthalate (DINP), and genistein (GEN) in maternal diet on rat offspring, and found developmental and/or reproductive toxicity with 0.5 ppm EE, 1200 ppm MXC, and 20,000 ppm DINP. Although the toxicological profile with MXC was similar to the EE case, the population changes in pituitary hormone-producing cells totally differed between the two cases, changes being evident from 240 ppm with MXC. In the present study, to assess the impact of these agents on brain sexual differentiation, region-specific mRNA expression of estrogen receptors (ER) alpha and beta, the progesterone receptor (PR), gonadotrophin-releasing hormone, steroid receptor coactivators (SRC)-1 and -2, and calbindin-D in microdissected hypothalamic medial preoptic areas (MPOAs) at postnatal day 10 was first analyzed in rats exposed to 0.5 ppm-EE from gestational day 15 by real-time RT-PCR. Sexually dimorphic expression of ER alpha and PR was noted with predominance in females and males, respectively, EE up-regulating SRC-1 in males and ER beta and PR in females. Next, we similarly examined expression changes of ER alpha and beta, PR, and SRC-1 in animals exposed to MXC at 24, 240, and 1200 ppm, DINP at 4000 and 20,000 ppm, and GEN at 1000 ppm. MXC at 1200 ppm down- and up-regulated PR in males and females, respectively, and DINP at 20,000 ppm down-regulated PR in females, while GEN did not exert any clear effects. The results thus suggest that agents causing developmental and/or reproductive abnormalities in later life may affect hypothalamic PR expression during the exposure period in early life.

  16. Association of Progesterone, Pessary, and Antibiotic for Treating Pregnant Woman with Short Cervix Syndrome: Importance of Magnetic Resonance Imaging in the Assessment of Pessary Position

    Directory of Open Access Journals (Sweden)

    Edward Araujo Júnior

    2013-01-01

    Full Text Available Preterm delivery (PD is the most important cause of neonatal mortality, particularly before the 32 nd week of pregnancy. A short cervix is the most important quantitative marker for predicting PD. However, there are other qualitative markers such as cervical gland area, cervical funneling, and sludge. We present the case of a pregnant woman who was diagnosed with a short cervix at 14-weeks and demonstrate the use of triple therapy, which helped to achieve a good perinatal result. A 37-year-old pregnant woman (G3P0 was referred to our service at 14-weeks of pregnancy presenting with a short cervix (20 mm and a positive sludge sign. She was hospitalized; a pessary was inserted, and started on antibiotic therapy (clindamycin and cefalotin for 10 days. At 20 weeks, she was again admitted to the hospital, and this time presented with a further shortened cervix (9 mm, cervical funneling, and a positive sludge sign, with the pessary in position. The following procedures were performed: Amniocentesis on the sludge (negative bacterioscopy, another cycle of antibiotics, administration of oral progesterone, and imaging to determine retention of pessary position. The patient was placed in the Trendelenburg position and remained hospitalized for 82 days. At 32 + 1 weeks, the fetus presented distress (tachycardia. C-section was performed, producing a live female newborn weighing 2,180 g and presenting Apgar indexes of 8/8. This case report demonstrates the importance of magnetic resonance imaging to assess the position of pessary in a pregnant woman with short cervix.

  17. No association between the progesterone receptor gene polymorphism (+331G/a) and the risk of breast cancer: an updated meta-analysis.

    Science.gov (United States)

    Qi, Xing-Ling; Yao, Jun; Zhang, Yong

    2017-10-30

    Many published studies have estimated the association between the +331G/A (rs10895068) polymorphism in the progesterone receptor (PgR) gene and breast cancer risk. However, the results remain inconsistent and controversial. To address this inconsistency, we systematically interrogated the aforementioned association via a meta-analysis. Through a literature search, we identified 13 case-control studies, including 12,453 cases and 14,056 case-free controls. The strengths of reported associations were evaluated using odds ratios (ORs) with 95% confidence intervals (95%CIs). An association was found between +331G/A polymorphism and +331G/A risk in the dominant model (p = 0.027). Via subgroup analysis, we found no association between +331G/A and breast cancer risk in Caucasians, Asians or mixed racial groups. Through meta-analysis, we were able to gain insight into previously reported associations between +331G/A polymorphism and breast cancer risk. However, further studies are still needed to provide more evidence.

  18. Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women.

    Science.gov (United States)

    Brache, Vivian; Sitruk-Ware, Regine; Williams, Alistair; Blithe, Diana; Croxatto, Horacio; Kumar, Narender; Kumar, Sushma; Tsong, Yun-Yen; Sivin, Irving; Nath, Anita; Sussman, Heather; Cochon, Leila; Miranda, Maria Jose; Reyes, Verónica; Faundes, Anibal; Mishell, Daniel

    2012-05-01

    Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation. This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated. Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%). In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women's Health Study: how many kinds of breast cancer are there?

    Science.gov (United States)

    Potter, J D; Cerhan, J R; Sellers, T A; McGovern, P G; Drinkard, C; Kushi, L R; Folsom, A R

    1995-06-01

    Characterization of breast tumors on both estrogen receptor (ER) and progesterone receptor (PR) status suggests distinct biological and clinical profiles. We hypothesized that these tumor subtypes might also show specific differences in their relations with epidemiologic risk factors. Risk factors were assessed via a questionnaire mailed in January 1986 to 37,105 cancer-free women, ages 55-69 years: the Iowa Women's Health Study. To the end of 1992 (241,627 person-years of follow-up), 939 incident breast cancers were ascertained by the Iowa population-based Surveillance, Epidemiology, and End Results Cancer Registry. Joint ER and PR status was determined on a total of 610 (65%) tumors. Three patterns of association were seen in relation to epidemiologic risk factors. Endogenous hormone exposure variables--parity, age at first birth, age at menarche, body mass index, and body fat distribution as defined by waist-to-hip ratio--showed their expected pattern of associations only with PR+ breast cancers. In age- adjusted and polychotomous logistic regression analyses, both ER-PR- and ER+PR- breast cancers showed evidence of an inverted pattern of associations with several risk factors compared with that seen for ER+PR+ cancers [including parity (ER-PR-), waist-to-hip ratio (ER-PR-), body mass index (both), body mass index at age 18 years (ER-PR-), history of bilateral oophorectomy (ER+PR-), and oral contraceptive use (ER+PR-)]. Family history was not associated with ER+PR- cancers; only 8 (8%) of 99 patients with this subtype had a family history of breast cancer compared with 16% of all other types combined.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. The CRH-R₁ receptor mediates luteinizing hormone, prolactin, corticosterone and progesterone secretion induced by restraint stress in estrogen-primed rats.

    Science.gov (United States)

    Traslaviña, Guillermo A Ariza; Franci, Celso Rodrigues

    2011-11-03

    Acute stress has been shown to modify hypothalamus-pituitary-gonadal (HPG) axis activity. Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamus-pituitary-adrenal (HPA) axis, has been implicated as a mediator of stress-induced effects on the reproductive axis. The role of the specific CRH receptor subtypes in this response is not completely understood. In the current study, we investigated the role of the CRH-R(1) receptor on luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), progesterone (P) and corticosterone (CT) secretion in stress-induced responses under the influence of estrogen (E(2)). Estrogen-primed ovariectomized rats (estradiol cypionate, 10 μg sc) received an i.v. administration of antalarmin (0.1 or 1mg/kg), a selective CRH-R(1) antagonist, or vehicle before restraint stress for 40 min. Seven blood samples were collected from two experimental groups (one from 10:00 h to 14:00 h and the other from 10:00 h to 18:00 h). An increase of plasma LH induced by restraint acute-stress was followed by alteration of the secretion pattern in the estrogen-induced afternoon surge. In a similar manner, we observed a suppression of the afternoon surge in plasma FSH, a delay of E(2)-induced PRL secretion, and an increase in plasma P and CT. Antalarmin attenuated stress-induce LH increase, decreased CT and P secretion and blocked the stress effects on PRL secretion. These findings suggest that CRH-R(1) mediates, at least in part, the restraint stress effects on the HPA, PRL, and reproductive axes. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. The expression of CXCR4 is induced by the luteinizing hormone surge and mediated by progesterone receptors in human preovulatory granulosa cells.

    Science.gov (United States)

    Choi, Yohan; Park, Ji Yeon; Wilson, Kalin; Rosewell, Katherine L; Brännström, Mats; Akin, James W; Curry, Thomas E; Jo, Misung

    2017-06-01

    The chemokine CXC motif ligand 12 (CXCL12) and its cognate receptor, CXCR4, have been implicated in the ovulatory process in various animal models. However, little is known about the expression and regulation of CXCL12 and CXCR4 and their functions during the ovulatory period in the human ovary. In this study, we characterized the expression patterns of CXCL12 and CXCR4 in preovulatory follicles collected before the luteinizing hormone (LH) surge and at defined hours after hCG administration in women with the regular menstrual cycle. The levels of mRNA and protein for CXCR4 were increased in granulosa cells of late ovulatory follicles, whereas CXCL12 expression was constant in follicles throughout the ovulatory period. Both CXCR4 and CXCL12 were localized to a subset of leukocytes around and inside the vasculature of human preovulatory follicles. Using a human granulosa cell culture model, the regulatory mechanisms and functions of CXCL12 and CXCR4 expression were investigated. Human chorionic gonadotropin (hCG) stimulated CXCR4 expression, whereas CXCL12 expression was not affected, mimicking in vivo expression patterns. Both RU486 (progesterone receptor antagonist) and CoCl2 (HIFs activator) blocked the hCG-induced increase in CXCR4 expression, whereas AG1478 (EGFR inhibitor) had no effect. The treatment with CXCL12 had no effect on granulosa cell viability but decreased hCG-stimulated CXCR4 expression. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Differential regulation of breast cancer-associated genes by progesterone receptor isoforms PRA and PRB in a new bi-inducible breast cancer cell line.

    Directory of Open Access Journals (Sweden)

    Junaid A Khan

    Full Text Available Progesterone receptor isoforms (PRA and PRB are expressed at equal levels in normal mammary cells. However, alteration in PRA/PRB expression is often observed in aggressive breast cancer suggesting differential contribution of PR isoforms in carcinogenesis. The mechanisms underlying such processes remain to be established mainly due to paucity of appropriate cellular models. To investigate the role of PR isoforms and the impact of imbalanced PRA/PRB ratio in transcriptional regulation, we have generated an original human breast cancer cell line conditionally expressing PRA and/or PRB in dose-dependence of non-steroid inducers. We first focused on PR-dependent transcriptional regulation of the paracrine growth factor gene amphiregulin (AREG playing important role in cancer. Interestingly, unliganded PRA increases AREG expression, independently of estrogen receptor, yet inhibitable by antiprogestins. We show that functional outcome of epidermal growth factor (EGF on such regulation is highly dependent on PRA/PRB ratio. Using this valuable model, genome-wide transcriptomic studies allowed us to determine the differential effects of PRA and PRB as a function of hormonal status. We identified a large number of novel PR-regulated genes notably implicated in breast cancer and metastasis and demonstrated that imbalanced PRA/PRB ratio strongly impact their expression predicting poor outcome in breast cancer. In sum, our unique cell-based system strongly suggests that PRA/PRB ratio is a critical determinant of PR target gene selectivity and responses to hormonal/growth factor stimuli. These findings provide molecular support for the aggressive phenotype of breast cancers with impaired expression of PRA or PRB.

  3. Genome-wide progesterone receptor binding: cell type-specific and shared mechanisms in T47D breast cancer cells and primary leiomyoma cells.

    Directory of Open Access Journals (Sweden)

    Ping Yin

    Full Text Available BACKGROUND: Progesterone, via its nuclear receptor (PR, exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells. PRINCIPAL FINDINGS: ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and β were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs, whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2, a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types. CONCLUSIONS: Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in

  4. Estrogen and progesterone receptor-binding sites on the chicken vitellogenin II gene: synergism of steroid hormone action.

    OpenAIRE

    Cato, A C; Heitlinger, E; Ponta, H; Klein-Hitpass, L; Ryffel, G U; Bailly, A; Rauch, C; Milgrom, E

    1988-01-01

    The chicken vitellogenin II gene is transcriptionally activated by estrogens. In transient transfection experiments in human T47D cells that contain receptors for various steroids, we showed estradiol, progestin, and androgen responses of a chimeric chicken vitellogenin II construct. This construct consists of DNA sequences from -626 to -590 upstream of the start of transcription of the chicken vitellogenin gene linked to the herpes simplex virus thymidine kinase promoter driving the transcri...

  5. hCG activates Epac-Erk1/2 signaling regulating Progesterone Receptor expression and function in human endometrial stromal cells.

    Science.gov (United States)

    Tapia-Pizarro, Alejandro; Archiles, Sebastián; Argandoña, Felipe; Valencia, Cecilia; Zavaleta, Keyla; Cecilia Johnson, M; González-Ramos, Reinaldo; Devoto, Luigi

    2017-06-01

    How does hCG signal in human endometrial stromal cells (ESCs) and what is its role in regulating ESC function? hCG signaling in ESCs activates the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) pathway through exchange protein activated by cyclic AMP (cAMP) (Epac) and transiently increases progesterone receptor (PR) transcript and protein expression and its transcriptional function. hCG is one of the earliest embryo-derived secreted signals in the endometrium, which abundantly expresses LH/hCG receptors. hCG signals through cAMP/protein kinase A (PKA) in gonadal cells, but in endometrial epithelial cells, hCG induces Erk1/2 activation independent of the cAMP/PKA pathway. Few data exist concerning the signal transduction pathways triggered by hCG in ESCs and their role in regulation of ESC function. This is an in vitro study comprising patients undergoing benign gynecological surgery (n = 46). Endometrial samples were collected from normal cycling women during the mid-secretory phase for ESCs isolation. The study conducted in an academic research laboratory within a tertiary-care hospital. The activation of the Erk1/2 signal transduction pathway elicited by hCG was evaluated in ESC. Signaling pathway inhibitors were used to examine the roles of PKA, PI3K, PKC, adenylyl cyclase and Epac on the hCG-stimulated up-regulation of phospho-Erk1/2 (pErk1/2). Erk1/2 phosphorylation was determined by immunoblot. siRNA targeting Epac was used to investigate the molecular mechanisms. To assess the role of Erk1/2 signaling induced by hCG on ESC function, gene expression regulation was examined by immunofluorescence and real-time quantitative PCR. The role of PR on the regulation of transcript levels was studied using progesterone and the PR antagonist RU486. All experiments were conducted using at least three different cell culture preparations in triplicate. Addition of hCG to ESCs in vitro induced the phosphorylation of Erk1/2 through cAMP accumulation. Such

  6. The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor.

    Directory of Open Access Journals (Sweden)

    Yashini Govender

    Full Text Available Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN. We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4 in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR, and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼ 24 nM for transactivation of the anti-inflammatory GILZ gene and ∼ 4-20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence

  7. A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator, Ulipristal acetate. Research for a novel estrogen-free, method of contraception

    Science.gov (United States)

    Huang, YongMei; Jensen, Jeffrey T.; Brache, Vivian; Cochon, Leila; Williams, Alistair; Miranda, Maria-José; Croxatto, Horacio; Kumar, Narender; Sussman, Heather; Hoskin, Elena; Plagianos, Marlena; Roberts, Kevin; Merkatz, Ruth; Blithe, Diana; Sitruk-Ware, Regine

    2014-01-01

    Objective To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. Study Design This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500μg/day) or a high-dose (2500μg/d) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. Results All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. Conclusion The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500 μg/d ring. PMID:25193534

  8. Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation.

    Science.gov (United States)

    Courtoy, Guillaume E; Donnez, Jacques; Marbaix, Etienne; Barreira, Matilde; Luyckx, Mathieu; Dolmans, Marie-Madeleine

    2017-12-11

    To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo. © 2017 S. Karger AG, Basel.

  9. Evaluation of estrogen receptor alpha and beta and progesterone receptor expression and correlation with clinicopathologic factors and proliferative marker Ki-67 in breast cancers

    DEFF Research Database (Denmark)

    Rosa, Fabíola E; Caldeira, José R F; Felipes, Joice

    2008-01-01

    To elucidate the molecular profile of hormonal steroid receptor status, we analyzed ER-alpha, ER-beta, and PGR mRNA and protein expression in 80 breast carcinomas using reverse transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR, and immunohistochemical analysis. Qualitative ana...

  10. Progesterone Induces Scolex Evagination of the Human Parasite Taenia solium: Evolutionary Implications to the Host-Parasite Relationship

    Science.gov (United States)

    Escobedo, Galileo; Camacho-Arroyo, Ignacio; Hernández-Hernández, Olivia Tania; Ostoa-Saloma, Pedro; García-Varela, Martín; Morales-Montor, Jorge

    2010-01-01

    Taenia solium cysticercosis is a health problem in underdeveloped and developed countries. Sex hormones are involved in cysticercosis prevalence in female and male pigs. Here, we evaluated the effects of progesterone and its antagonist RU486 on scolex evagination, which is the initial step in the development of the adult worm. Interestingly, progesterone increased T. solium scolex evagination and worm growth, in a concentration-independent pattern. Progesterone effects could be mediated by a novel T. solium progesterone receptor (TsPR), since RU486 inhibits both scolex evagination and worm development induced by progesterone. Using RT-PCR and western blot, sequences related to progesterone receptor were detected in the parasite. A phylogenetic analysis reveals that TsPR is highly related to fish and amphibian progesterone receptors, whereas it has a distant relation with birds and mammals. Conclusively, progesterone directly acts upon T. solium cysticerci, possibly through its binding to a progesterone receptor synthesized by the parasite. PMID:20037735

  11. Progesterone Induces Scolex Evagination of the Human Parasite Taenia solium: Evolutionary Implications to the Host-Parasite Relationship

    Directory of Open Access Journals (Sweden)

    Galileo Escobedo

    2010-01-01

    Full Text Available Taenia solium cysticercosis is a health problem in underdeveloped and developed countries. Sex hormones are involved in cysticercosis prevalence in female and male pigs. Here, we evaluated the effects of progesterone and its antagonist RU486 on scolex evagination, which is the initial step in the development of the adult worm. Interestingly, progesterone increased T. solium scolex evagination and worm growth, in a concentration-independent pattern. Progesterone effects could be mediated by a novel T. solium progesterone receptor (TsPR, since RU486 inhibits both scolex evagination and worm development induced by progesterone. Using RT-PCR and western blot, sequences related to progesterone receptor were detected in the parasite. A phylogenetic analysis reveals that TsPR is highly related to fish and amphibian progesterone receptors, whereas it has a distant relation with birds and mammals. Conclusively, progesterone directly acts upon T. solium cysticerci, possibly through its binding to a progesterone receptor synthesized by the parasite.

  12. 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 ...

  13. The hyperplastic phenotype in PR-A and PR-B transgenic mice: lessons on the role of estrogen and progesterone receptors in the mouse mammary gland and breast cancer.

    Science.gov (United States)

    Sampayo, Rocio; Recouvreux, Sol; Simian, Marina

    2013-01-01

    Progesterone receptor (PR) belongs to the superfamily of steroid receptors and mediates the action of progesterone in its target tissues. In the mammary gland, in particular, PR expression is restricted to the luminal epithelial cell compartment. The generation of estrogen receptor-α (ER) and PR knockout mice allowed the specific characterization of the roles of each of these in mammary gland development: ER is critical for ductal morphogenesis, whereas PR has a key role in lobuloalveolar differentiation. To further study the role PR isoforms have in mammary gland biology, transgenic mice overexpressing either the "A" (PR-A) or the "B" (PR-B) isoforms of PR were generated. Overexpression of the A isoform of PR led to increased side branching, multilayered ducts, loss of basement membrane integrity, and alterations in matrix metalloproteinase activation in the mammary gland. Moreover, levels of TGFβ1 and p21 were diminished and those of cyclin D1 increased. Interestingly, the phenotype was counteracted by antiestrogens, suggesting that ER is essential for the manifestation of the hyperplasias. Mice overexpressing the B isoform of PR had limited ductal growth but retained the ability to differentiate during pregnancy. Levels of latent and active TGFβ1 were increased compared to PR-A transgenics. The phenotypes of these transgenic mice are further discussed in the context of the impact of progesterone on mammary stem cells and breast cancer. We conclude that an adequate balance between the A and B isoforms of PR is critical for tissue homeostasis. Future work to further understand the biology of PR in breast biology will hopefully lead to new and effective preventive and therapeutic alternatives for patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Endocrine disruption: In silico perspectives of interactions of di-(2-ethylhexyl)phthalate and its five major metabolites with progesterone receptor.

    Science.gov (United States)

    Sheikh, Ishfaq A; Abu-Elmagd, Muhammad; Turki, Rola F; Damanhouri, Ghazi A; Beg, Mohd A; Al-Qahtani, Mohammed

    2016-09-30

    Di-(2-ethylhexyl)phthalate (DEHP) is a common endocrine disrupting compound (EDC) present in the environment as a result of industrial activity and leaching from polyvinyl products. DEHP is used as a plasticizer in medical devices and many commercial and household items. Exposure occurs through inhalation, ingestion, and skin contact. DEHP is metabolized to a primary metabolite mono-(2-ethylhexyl)phthalate (MEHP) in the body, which is further metabolized to four major secondary metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5-OH-MEHP), mono(2-ethyl-5-oxyhexyl)phthalate (5-oxo-MEHP), mono(2-ethyl-5-carboxypentyl)phthalate (5-cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2-cx-MMHP). DEHP and its metabolites are associated with developmental abnormalities and reproductive dysfunction within the human population. Progesterone receptor (PR) signaling is involved in important reproductive functions and is a potential target for endocrine disrupting activities of DEHP and its metabolites. This study used in silico approaches for structural binding analyses of DEHP and its five indicated major metabolites with PR. Protein Data bank was searched to retrieve the crystal structure of human PR (Id: 1SQN). PubChem database was used to obtain the structures of DEHP and its five metabolites. Docking was performed using Glide (Schrodinger) Induced Fit Docking module. DEHP and its metabolites interacted with 19-25 residues of PR with the majority of the interacting residues overlapping (82-95 % commonality) with the native bound ligand norethindrone (NET). DEHP and each of its five metabolites formed a hydrogen bonding interaction with residue Gln-725 of PR. The binding affinity was highest for NET followed by DEHP, 5-OH-MEHP, 5-oxo-MEHP, MEHP, 5-cx-MEPP, and 2-cx-MMHP. The high binding affinity of DEHP and its five major metabolites with PR as well as a high rate of overlap between PR interacting residues among DEHP and its metabolites and the native ligand, NET

  15. A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception.

    Science.gov (United States)

    Huang, YongMei; Jensen, Jeffrey T; Brache, Vivian; Cochon, Leila; Williams, Alistair; Miranda, Maria-José; Croxatto, Horacio; Kumar, Narender; Sussman, Heather; Hoskin, Elena; Plagianos, Marlena; Roberts, Kevin; Merkatz, Ruth; Blithe, Diana; Sitruk-Ware, Regine

    2014-12-01

    To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring. The 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. 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

  17. Progesterone for premenstrual syndrome

    NARCIS (Netherlands)

    Ford, Olive; Lethaby, Anne; Roberts, Helen; Mol, Ben Willem J.

    2009-01-01

    BACKGROUND: About 5% of women experience severe symptoms called premenstrual syndrome (PMS), only in the two weeks before their menstrual periods. Treatment with progesterone may restore a deficiency, balance menstrual hormone levels or reduce effects of falling progesterone levels on the brain or

  18. Progesterone Exerts a Neuromodulatory Effect on Turning Behavior of Hemiparkinsonian Male Rats: Expression of 3α-Hydroxysteroid Oxidoreductase and Allopregnanolone as Suggestive of GABAA Receptors Involvement

    Directory of Open Access Journals (Sweden)

    Roberto Yunes

    2015-01-01

    Full Text Available There is a growing amount of evidence for a neuroprotective role of progesterone and its neuroactive metabolite, allopregnanolone, in animal models of neurodegenerative diseases. By using a model of hemiparkinsonism in male rats, injection of the neurotoxic 6-OHDA in left striatum, we studied progesterone’s effects on rotational behavior induced by amphetamine or apomorphine. Also, in order to find potential explanatory mechanisms, we studied expression and activity of nigrostriatal 3α-hydroxysteroid oxidoreductase, the enzyme that catalyzes progesterone to its active metabolite allopregnanolone. Coherently, we tested allopregnanolone for a possible neuromodulatory effect on rotational behavior. Also, since allopregnanolone is known as a GABAA modulator, we finally examined the action of GABAA antagonist bicuculline. We found that progesterone, in addition to an apparent neuroprotective effect, also increased ipsilateral expression and activity of 3α-hydroxysteroid oxidoreductase. It was interesting to note that ipsilateral administration of allopregnanolone reversed a clear sign of motor neurodegeneration, that is, contralateral rotational behavior. A possible GABAA involvement modulated by allopregnanolone was shown by the blocking effect of bicuculline. Our results suggest that early administration of progesterone possibly activates genomic mechanisms that promote neuroprotection subchronically. This, in turn, could be partially mediated by fast, nongenomic, actions of allopregnanolone acting as an acute modulator of GABAergic transmission.

  19. Progesterone resistance in endometriosis

    DEFF Research Database (Denmark)

    Patel, Bansari G; Rudnicki, Martin; Yu, Jie

    2017-01-01

    Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women...... renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone resistant state...... and their targets. Environmental toxins, such as dioxin, play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins...

  20. 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.

  1. Influence of estradiol, progesterone, and nutrition on concentrations of gonadotropins and GnRH receptors, and abundance of mRNA for GnRH receptors and gonadotropin subunits in pituitary glands of beef cows.

    Science.gov (United States)

    Looper, M L; Vizcarra, J A; Wettemann, R P; Malayer, J R; Braden, T D; Geisert, R D; Morgan, G L

    2003-01-01

    Nutritionally induced anovulatory cows (n = 28) were used to determine the effect of steroids on regulation of synthesis and secretion of gonadotropins. Anovulatory cows were ovariectomized and received intravaginal inserts containing estradiol (E2), progesterone (P4), E2 and P4 (E2P4), or a sham intravaginal insert (C) for 7 d. Concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were quantified in serum and E2 and P4 were quantified in plasma. Cows were exsanguinated within 1 to 2 h after removal of intravaginal inserts and pituitary glands were collected and stored at -80 degrees C until messenger ribonucleic acid (mRNA) for gonadotropin-releasing hormone receptor (GnRH-R) and gonadotropin subunits, pituitary content of GnRH-R, and LH and FSH were quantified. Pituitary glands from five proestrous cows were harvested to compare gonadotropin characteristics between ovariectomized, anovulatory cows and intact cows. Plasma concentrations of E2 were greater (P cows than in sham-treated cows. Concentrations of P4 were greater (P cows treated with P4 than in sham-treated cows. Mean serum concentrations of LH and FSH were not significantly influenced by steroid treatments. However, frequency of LH pulses of ovariectomized, nutritionally induced anovulatory cows was increased (P cows treated with E2 or P4 than in cows treated with E2P4 or sham-treated. Quantity of mRNA for LHbeta in the pituitary gland was greater when cows were treated with P4. Concentrations of LH in the pituitary gland were not affected by steroid treatments; however, pituitary concentrations of FSH were less (P cows than in sham-treated cows. The number of GnRH-R was increased (P cows treated with E2, but P4 treatment did not influence the number of GnRH-R. Abundance of mRNA for GnRH-R, common alpha-subunit, and FSHbeta were not affected by treatments. Pituitary concentrations of LH were greater (P cows than in ovariectomized, anovulatory cows treated with or without

  2. 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

    Consortium. METHODS: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness...... and histopathology were assessed using logistic regression. RESULTS: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive...

  3. Breast cancer among nurses: is the intensity of night work related to hormone receptor status?

    Science.gov (United States)

    Lie, Jenny-Anne S; Kjuus, Helge; Zienolddiny, Shan; Haugen, Aage; Kjærheim, Kristina

    2013-07-01

    The aim of this study was to investigate whether night work is related to breast cancer receptor status. The effect of night work on the risk of estrogen receptor- and progesterone receptor-defined breast cancers was evaluated in 513 nurses diagnosed with breast cancer between 1996 and 2007 and in 757 frequency-matched controls, all of whom were selected from a cohort of Norwegian nurses. Odds ratios for the exposure "duration of work with a minimum of 6 consecutive night shifts" were compared for tumor subgroups with respect to the common control group through the use of polytomous logistic regression. Statistically significant associations were observed between breast cancer and work durations of ≥ 5 years with ≥ 6 consecutive night shifts, with the highest risk observed for progesterone receptor-positive tumors (odds ratio = 2.4, 95% confidence interval: 1.3, 4.3; P-trend = 0.01). When the exposure variable was dichotomized (ever/never worked ≥ 6 consecutive night shifts), a borderline statistically significant heterogeneity (P = 0.05) was seen between progesterone receptor-positive and progesterone receptor-negative tumors in postmenopausal women. The association observed between consecutive night shifts and progesterone receptor-positive cancers suggests that progesterone could play an important role in the detrimental effects of night work.

  4. Uses of progesterone in clinical practice.

    Science.gov (United States)

    Warren, M P; Shantha, S

    1999-01-01

    Progesterone is the natural progestagen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in unphysiologically high levels of progesterone metabolites, particularly those reduced at the 5-a position. These metabolites can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate (NETA), have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this problem, synthetic progestins such as NETA have been administered transdermally. These compounds, though, just like synthetic estrogens administered non-orally, retain undesirable hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories, which lack manufacturing controls. Recently, a new progesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characteristics of its polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, this formulation given in conjunction with physiological amounts of estradiol produces endometrial changes similar to

  5. 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

  6. Progesterone induces adult mammary stem cell expansion.

    Science.gov (United States)

    Joshi, Purna A; Jackson, Hartland W; Beristain, Alexander G; Di Grappa, Marco A; Mote, Patricia A; Clarke, Christine L; Stingl, John; Waterhouse, Paul D; Khokha, Rama

    2010-06-10

    Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown. Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.

  7. Progesterone receptor membrane component 1 (PGRMC1) expression in fetal membranes among women with preterm premature rupture of the membranes (PPROM).

    Science.gov (United States)

    Feng, L; Antczak, B C; Lan, L; Grotegut, C A; Thompson, J L; Allen, T K; Murtha, A P

    2014-05-01

    PGRMC1 function is implicated in maintaining fetal membrane (FM) integrity. PGRMC1 was detectable primarily in the cytoplasm of FM cells and was actively regulated in FMs and relevant for PGRMC1-mediated progesterone action. By cell type, PGRMC1 expression was higher in amnion and chorion compared with decidua. By clinical phenotype, PGRMC1 expression was higher among preterm-no-labor and term-no-labor subjects compared to PPROM. PGRMC1 expression appears to be diminished in PPROM subjects. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. 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.

  9. Decreased endogenous progesterone and ratio of progesterone to ...

    African Journals Online (AJOL)

    PRECIOUS

    2010-02-01

    Feb 1, 2010 ... Progesterone and estrogen are two steroid hormones whose exposure may decrease the risk and delay the onset of ischemic stroke. The main objective of this study was to determine the plasma level of progesterone, estrogen and ratio of progesterone/estrogen in ischemic stroke patients. The plasma.

  10. Decreased endogenous progesterone and ratio of progesterone to ...

    African Journals Online (AJOL)

    Progesterone and estrogen are two steroid hormones whose exposure may decrease the risk and delay the onset of ischemic stroke. The main objective of this study was to determine the plasma level of progesterone, estrogen and ratio of progesterone/estrogen in ischemic stroke patients. The plasma levels of ...

  11. Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.

    Directory of Open Access Journals (Sweden)

    Paul H van der Horst

    Full Text Available BACKGROUND: Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs as well as progesterone receptor (PR positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT. METHODOLOGY AND PRINCIPAL FINDINGS: Paraffin sections from patients with (n = 9 or without (n = 9 progressive endometrial cancer (recurrent or metastatic disease were assessed for the presence of CD4+ (helper, CD8+ (cytotoxic and Foxp3+ (regulatory T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK endometrial cancer cell lines stably transfected with PRA (IKPRA, PRB (IKPRB and PRA+PRB (IKPRAB were cultured in presence/absence of progesterone (MPA and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling. CONCLUSION: Intact progesterone signaling in non

  12. Rodent Models of Non-classical Progesterone Action Regulating Ovulation

    Directory of Open Access Journals (Sweden)

    Melinda A. Mittelman-Smith

    2017-07-01

    Full Text Available It is becoming clear that steroid hormones act not only by binding to nuclear receptors that associate with specific response elements in the nucleus but also by binding to receptors on the cell membrane. In this newly discovered manner, steroid hormones can initiate intracellular signaling cascades which elicit rapid effects such as release of internal calcium stores and activation of kinases. We have learned much about the translocation and signaling of steroid hormone receptors from investigations into estrogen receptor α, which can be trafficked to, and signal from, the cell membrane. It is now clear that progesterone (P4 can also elicit effects that cannot be exclusively explained by transcriptional changes. Similar to E2 and its receptors, P4 can initiate signaling at the cell membrane, both through progesterone receptor and via a host of newly discovered membrane receptors (e.g., membrane progesterone receptors, progesterone receptor membrane components. This review discusses the parallels between neurotransmitter-like E2 action and the more recently investigated non-classical P4 signaling, in the context of reproductive behaviors in the rodent.

  13. [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

  14. 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

  15. Effect of hyperthyroidism on circulating prolactin and hypothalamic expression of tyrosine hydroxylase, prolactin signaling cascade members and estrogen and progesterone receptors during late pregnancy and lactation in the rat.

    Science.gov (United States)

    Pennacchio, Gisela E; Neira, Flavia J; Soaje, Marta; Jahn, Graciela A; Valdez, Susana R

    2017-02-15

    Hyperthyroidism (HyperT) compromises pregnancy and lactation, hindering suckling-induced PRL release. We studied the effect of HyperT on hypothalamic mRNA (RT-qPCR) and protein (Western blot) expression of tyrosine hydroxylase (TH), PRL receptor (PRLR) and signaling pathway members, estrogen-α (ERα) and progesterone (PR) receptors on late pregnancy (days G19, 20 and 21) and early lactation (L2) in rats. HyperT advanced pre-partum PRL release, reduced circulating PRL on L2 and increased TH mRNA (G21 and L2), p-TH, PRLR mRNA, STAT5 protein (G19 and L2), PRLR protein (G21) and CIS protein (G19). PRs mRNAs and protein decreased on G19 but afterwards PRA mRNA (G20), PRB mRNA (G21) and PRA mRNA and protein (L2) increased. ERα protein increased on G19 and decreased on G20. Thus, the altered hypothalamic PRLR, STAT5, PR and ERα expression in hyperthyroid rats may induce elevated TH expression and activation, that consequently, elevate dopaminergic tone during lactation, blunting suckling-induced PRL release and litter growth. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

    Science.gov (United States)

    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

  17. [Transcriptional regulation effect of THSG and anthraquinones in tubers of Polygonum multiflorum based on human progesterone X receptor (PXR) mediated CYP3A4 rapid screening system].

    Science.gov (United States)

    Zhang, Zhao-Yan; Yang, Liang; Huang, Xiao-Yan; Wang, Mei-Xi; Ma, Zeng-Chun; Tang, Xiang-Lin; Wang, Yu-Guang; Gao, Yue

    2017-12-01

    The rapid screening technology was used to investigate the transcriptional regulation effect of main chemical constituents in tubers of Polygonum multiflorum, including 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside(THSG) and anthraquinones (such as rhein, chrysophanol, aloe-emodin, emodin) on CYP3A4 drug inducers induced by human pregnancy X receptor (PXR).The effect of chemical composition on the cell activity was detected by MTS cell viability assay. IC₅₀ was calculated. The expression vector and the reporter vector were co-transfected into HepG2 cells, with 10 μmol•L⁻¹ rifampicin (RIF) as a positive control, and 10 μmol•L⁻¹ ketoconazole (TKZ) as a negative control. After treated with different concentrations of anthraquinones (2.5, 5, 10 μmol•L⁻¹) for 24 h, the cells were tested for dual luciferase activity. The results show that the inhibitory effect of THSG, chrysophanol, emodin, rhein and aloe-emodin on CYP3A4 was inhibited by co-transfection of pcDNA3.1 and pGL4.17-CYP3A4. The expressions of pcDNA3.14-PXR and pGL4.17-CYP3A4 were induced by the four compounds. Besides, emodin had a direct inducing effect. In conclusion, the four anthraquinone compounds have an inducing effect on CYP3A4 by PXR, but emodin can directly induce CYP3A4. THSG can inhibit CYP3A4, but plasmid can induce CYP3A4 after intervened with PXR.These results suggest that we should pay attention to the liver function and avoid liver damage in the combined administration of drugs. Copyright© by the Chinese Pharmaceutical Association.

  18. Women's Perspective on Progesterone: A Qualitative Study Conducted in Australia.

    Science.gov (United States)

    Spark, M Joy; Dunn, Rebecca A; Houlahan, Kelli L

    2009-01-01

    This study explored the perspective of women using compounded progesterone preparations. Semi-structured interviews were conducted in Victoria, Australia with eight self-selected women who were dispensed a progesterone-only preparation. Participating women gained symptome relief for migraine, painful breasts, mood swings, bloating, hot flushes, and other conditions. The participants also experienced unexpected benefits such as improvement in irregular and painful periods, relief from cystitis, or increased libido, without any reported negative side effects. The participants appreciated the ability to adjust the dose and dosage form to their individual requirements and held a positive perception of progesterone as a "natural" product. Accessibility of progesterone treatment is limited due to the limited number of doctors that have knowledge about the treatment, little information available for lay people, and cost. Participants who had been treated with progesterone were willing to share their experience with others, and many heard about progesterone therapy from their social contacts. The cost of progesterone therapy, which was often more expensive than traditional hormone replacement therapy, was outweighed by the benefits received. These women found that progesterone treatment, although hard to access, was beneficial over conventional therapy.

  19. Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF).

    Science.gov (United States)

    Cohen, Rachael A; Check, Jerome H; Dougherty, Michael P

    2016-02-01

    To determine if exposure to progesterone alone is sufficient to increase the production of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Also to determine what method of progesterone delivery or form of P best stimulates PIBF secretion. Serum samples from patients with infertility and paid volunteers were evaluated for both PIBF and progesterone at various times during the follicular phase and the luteal phase in both natural cycles and cycles involving embryo transfer after endogenous and exogenous progesterone exposure and after various synthetic progestins. PIBF was measured by a non-commercial research ELISA assay. Comparisons were made of serum PIBF before and after exposure to progesterone, 17-hydroxyprogesterone, and oral contraceptives. PIBF was also measured before and after transfer of embryos. Progesterone alone without exposure to the fetal allogeneic stimulus was able to produce a marked increase in serum PIBF. Neither a synthetic progestin (19-nortestosterone derivative) nor 17-hydroxyprogesterone caused an increase in PIBF. Some PIBF is generally detected even in the follicular phase. A previous concept considered that an allogeneic stimulus, e.g., from the fetal semi-allograft, was necessary to induce de novo progesterone receptors in gamma delta T cells, which, in turn, when exposed to a high concentration of progesterone, would secrete high levels of PIBF. These data show that exposure to an allogeneic stimulus is not needed to cause a marked rise in PIBF, merely progesterone alone is sufficient.

  20. [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.

  1. Progesterone modulation of diazepam withdrawal syndrome in mice.

    Science.gov (United States)

    Pesce, M E; Acevedo, X; Pinardi, G; Miranda, H F

    1996-12-01

    The influence of progesterone and oestrogens on the benzodiazepine withdrawal syndrome in mice was studied. The intraperitoneal administration of 15 mg/kg of flumazenil induced a withdrawal syndrome in chronic diazepam-treated mice, characterized by jerks, usually accompanied by tail lifts, and seizures. The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone as revealed by a low incidence of jerks and seizures. The action of progesterone could be due to a modulatory role of the hormone on neuronal activity as an anxiolytic agent. The modulatory activity of progesterone appears to be related to changes in the pharmacological properties of benzodiazepine receptors.

  2. 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 (...

  3. 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...

  4. 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

  5. Progesterone and Mental Rotation Task: Is There Any Effect?

    Directory of Open Access Journals (Sweden)

    Donatas Noreika

    2014-01-01

    Full Text Available Mental rotation task (MRT incorporates elements of spatial abilities, important in many professions, with people of both genders involved. Importantly, these are the areas where spatial tasks might be performed for long time periods; thus adverse effects of mental fatigue are highly unwanted. Substantial variation of MRT performance in relation to estrogen levels has been observed in many studies, whereas the role of progesterone remains elusive. Here we aimed to elucidate the effect of progesterone level on the long-duration (1.5 hours performance of MRT. We included three groups of subjects: a group of males as a control, a group of females in their follicular phase (low progesterone and a group of females in their luteal phase (high progesterone, MRT accuracy and response time, subjective fatigue ratings and cardiovascular measures together with 17β-estradiol and progesterone concentrations were analyzed. We found that subjective ratings of fatigue increased, performance accuracy increased, and mean response times decreased during the task in all groups. Females in luteal phase were significantly slower not only than men, but also than females in their follicular phase. An increase in subjective fatigue ratings was positively related to progesterone level—at higher progesterone levels, females felt more tired.

  6. The role of progesterone in prevention of preterm birth

    Directory of Open Access Journals (Sweden)

    Jodie M Dodd

    2009-07-01

    Full Text Available Jodie M Dodd, Caroline A CrowtherDiscipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, South Australia, AustraliaAbstract: Preterm birth continues to provide an enormous challenge in the delivery of perinatal health care, and is associated with considerable short and long-term health consequences for surviving infants. Progesterone has a role in maintaining pregnancy, by suppression of the calcium–calmodulin–myosin light chain kinase system. Additionally, progesterone has recognized anti-inflammatory properties, raising a possible link between inflammatory processes, alterations in progesterone receptor expression and the onset of preterm labor. Systematic reviews of randomized controlled trials evaluating the use of intramuscular and vaginal progesterone in women considered to be at increased risk of preterm birth have been published, with primary outcomes of perinatal death, preterm birth <34 weeks, and neurodevelopmental handicap in childhood. Eleven randomized controlled trials were included in the systematic review, involving 2714 women and 3452 infants, with results presented according to the reason women were considered to be at increased risk of preterm birth. While there is a potential beneficial effect in the use of progesterone for some women considered to be at increased risk of preterm birth, primarily in the reduction in the risk of preterm birth before 34 weeks gestation, it remains unclear if the observed prolongation of pregnancy translates into improved health outcomes for the infant.Keywords: progesterone, preterm birth, systematic review, randomized trial

  7. Searching for a functional relationship between the breast cancer susceptibility gene BRCA1 and the progesterone receptor in breast cancer cells

    OpenAIRE

    Calvo Vidal, Verónica Alejandra

    2009-01-01

    Mutaciones germinales en el gen breast cancer susceptibility gene BRCA1 aumentan altamente el riesgo de padecer cáncer de mama y ovario en mujeres. Se han propuesto diferentes hipótesis para explicar esta especificidad de tejido. Una de las hipótesis más argumentadas es la que propone una relación entre BRCA1 y la acción de las hormonas ováricas. En los últimos años se han publicado numerosos datos señalando al papel esencial del receptor de progesterona (PR) en la inducción del desarrollo no...

  8. Novel Hormone Receptors Present in Apocrine Cystadenoma of the Eyelid.

    Science.gov (United States)

    Brown, Sarah E; Friedman, Alan H; Phelps, Robert G; Bleiweiss, Ira J; Wu, Albert Y

    A 53-year-old woman presented with an apocrine cystadenoma of the right upper eyelid. Histologic examination revealed proliferating epithelial cells with apocrine snouts and occasional mitotic figures. Immunohistochemical analysis revealed a Ki-67 index of 15% and positive staining for synaptophysin, chromogranin, estrogen receptor, progesterone receptor, gross cystic disease fluid protein (GCDFP)-15, and mammoglobin. The complement of positive immunomarkers in this case reinforces the importance of total excision and careful histologic assessment.

  9. Intestinal tumorigenesis is not affected by progesterone signaling in rodent models.

    Directory of Open Access Journals (Sweden)

    Jarom Heijmans

    Full Text Available Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO to the Apc(Min/+ mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+ mice exhibited no change in polyp number, size or localization compared to Apc(Min/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

  10. Dietary fiber intake and risk of breast cancer defined by estrogen and progesterone receptor status: the Japan Public Health Center-based Prospective Study.

    Science.gov (United States)

    Narita, Saki; Inoue, Manami; Saito, Eiko; Abe, Sarah K; Sawada, Norie; Ishihara, Junko; Iwasaki, Motoki; Yamaji, Taiki; Shimazu, Taichi; Sasazuki, Shizuka; Shibuya, Kenji; Tsugane, Shoichiro

    2017-06-01

    Epidemiological studies have suggested a protective effect of dietary fiber intake on breast cancer risk while the results have been inconsistent. Our study aimed to investigate the association between dietary fiber intake and breast cancer risk and to explore whether this association is modified by reproductive factors and hormone receptor status of the tumor. A total of 44,444 women aged 45 to 74 years from the Japan Public Health Center-based Prospective Study were included in analyses. Dietary intake assessment was performed using a validated 138-item food frequency questionnaire (FFQ). Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer incidence were calculated by multivariate Cox proportional hazards regression models. During 624,423 person-years of follow-up period, 681 breast cancer cases were identified. After adjusting for major confounders for breast cancer risk, inverse trends were observed but statistically non-significant. Extremely high intake of fiber was associated with decreased risk of breast cancer but this should be interpreted with caution due to limited statistical power. In stratified analyses by menopausal and hormone receptor status, null associations were observed except for ER-PR- status. Our findings suggest that extreme high fiber intake may be associated with decreased risk of breast cancer but the level of dietary fiber intake among Japanese population might not be sufficient to examine the association between dietary fiber intake and breast cancer risk.

  11. 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.

  12. Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer

    Science.gov (United States)

    Kim, J. Julie; Kurita, Takeshi

    2013-01-01

    Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases. PMID:23303565

  13. 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

  14. 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...

  15. 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.

  16. 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

  17. Distinct cognitive effects of estrogen and progesterone in menopausal women.

    Science.gov (United States)

    Berent-Spillson, Alison; Briceno, Emily; Pinsky, Alana; Simmen, Angela; Persad, Carol C; Zubieta, Jon-Kar; Smith, Yolanda R

    2015-09-01

    The effects of postmenopausal hormone treatment on cognitive outcomes are inconsistent in the literature. Emerging evidence suggests that cognitive effects are influenced by specific hormone formulations, and that progesterone is more likely to be associated with positive outcomes than synthetic progestin. There are very few studies of unopposed progesterone in postmenopausal women, and none that use functional neuroimaging, a sensitive measure of neurobiological function. In this study of 29 recently postmenopausal women, we used functional MRI and neuropsychological measures to separately assess the effects of estrogen or progesterone treatment on visual and verbal cognitive function. Women were randomized to receive 90 days of either estradiol or progesterone counterbalanced with placebo. After each treatment arm, women were given a battery of verbal and visual cognitive function and working memory tests, and underwent functional MRI including verbal processing and visual working memory tasks. We found that both estradiol and progesterone were associated with changes in activation patterns during verbal processing. Compared to placebo, women receiving estradiol treatment had greater activation in the left prefrontal cortex, a region associated with verbal processing and encoding. Progesterone was associated with changes in regional brain activation patterns during a visual memory task, with greater activation in the left prefrontal cortex and right hippocampus compared to placebo. Both treatments were associated with a statistically non-significant increase in number of words remembered following the verbal task performed during the fMRI scanning session, while only progesterone was associated with improved neuropsychological measures of verbal working memory compared to placebo. These results point to potential cognitive benefits of both estrogen and progesterone. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Immunohistochemical expression of oestrogen and progesterone receptors during experimental acute and chronic murine Schistosomiasis mansoni Expressão imunohistoquímica de receptores para estrogênio e progesterona nas fases aguda e crônica da esquistossomose mansônica experimental em camundongos

    Directory of Open Access Journals (Sweden)

    Fawzia Ahmed Habib

    2010-10-01

    Full Text Available INTRODUCTION: The responsibility of Schistosoma mansoni in female infertility is still controversial. This study was conducted to evaluate the effect of acute and chronic schistosomiasis mansoni infection on the endometrium using immunohistochemical analysis of uterine hormone receptor expression. METHODS: Twenty-four nonpregnant swiss albino mice were divided into three groups: control, noninfected; acute; and chronic Schistosoma mansoni infection. Histological sections of uterine specimens were examined by light microscope with an image analyzing system to detect structural histological, estrogen receptor (ER and progesterone receptor (PR expression in the endometrium. RESULTS: No secretory phase was detected in the endometrium in acute and chronic Schistosoma infection. Hormone receptor expression (ER and PR showed statistically significant differences among the groups (pINTRODUÇÃO: A responsabilidade do Schistosoma mansoni em esterilidade feminina é ainda controversa. Este estudo é conduzido para avaliar o efeito da esquistossomose mansoni aguda e crônica no endométrio usando análise de imuno-histoquímíca da expressão de receptor hormonal uterina. MÉTODOS: Vinte e quatro camundongos fêmeas albinas suíças não grávidas foram divididas em 3 grupos (controle não-infectado, grupos agudos e crônicos infeccionados com Schistosoma mansoni. As seções histológicas de espécimes uterinos foram examinadas por microscópio leve com imagem, analisando sistema para detectar no endométrio expressões histológicas estruturais, receptor de estrogênio (ER e receptor de progesterona (PR. RESULTADOS: Nenhuma fase secretora foi detectada no endométrio com infecção aguda e crônica de Schistosoma. A expressão hormonal de receptor (ER e PR mostrou diferenças estatisticamente significantes entre grupos diferentes (p<0,05 com baixa significativa hormonal de ER com infecção crônica (comparado com controle proliferativo, controle secret

  19. 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.

  20. 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.

  1. 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.

  2. Progesterone is essential for protecting against LPS-induced pregnancy loss. LIF as a potential mediator of the anti-inflammatory effect of progesterone.

    Directory of Open Access Journals (Sweden)

    Julieta Aisemberg

    Full Text Available Lipopolysaccharide (LPS administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF, which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders.

  3. Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial.

    Science.gov (United States)

    Herzog, Andrew G

    2015-05-01

    To extend our knowledge and practical application of the concept of catamenial epilepsy. The review focuses on the impact of the NIH Progesterone Trial on our understanding of the pathophysiology and treatment of catamenial epilepsy. Catamenial epilepsy refers to the cyclic exacerbation of seizures in relation to the menstrual cycle. An interaction between seizures and the menstrual cycle is suggested by variations in seizure frequency according to the day, phase and ovulatory status of the menstrual cycle. There are three commonly recognized patterns: perimenstrual (C1: Day -3 to +3), peri-ovulatory (C2: Day 10 to 3) and entire luteal phase in anovulatory cycles (C3: Day 10 to 3). Pathophysiological determinants include 1) the neuroactive properties of reproductive steroids, 2) the variation of neuroactive steroid levels across the menstrual cycle and 3) the differential susceptibility of epileptic substrates to neuroactive steroid effects. Perimenstrual seizure exacerbation may result from the premenstrual withdrawal of progesterone which is accompanied by withdrawal of allopregnanolone, a potent positive allosteric modulator of the GABAA receptor, and changes in the subunit composition of the GABAA receptor to the α4 subtype which is insensitive to benzodiazepine and GABA. Bioidentical progesterone supplement is no better than placebo in the treatment of women with focal onset epilepsy overall but shows superior efficacy in women whose seizures show robust perimenstrual exacerbation. There is sound evidence for the existence of catamenial epilepsy and class 3 evidence for adjunctive progesterone treatment of the perimenstrually exacerbated subtype. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  4. 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

  5. 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

  6. Overview of progesterone profiles in dairy cows

    DEFF Research Database (Denmark)

    Blavy, P.; Derks, M.; Martin, O.

    2016-01-01

    kernel of three data points was used to smooth the progesterone time series. The time between start of progesterone rise and end of progesterone decline was identified by fitting a simple model consisting of base length and a quadratic curve to progesterone data, and this luteal like phase (LLP) was used...... to classify progesterone profiles without recourse to an a priori set of rules, which arbitrarily segment the natural variability in these profiles. Using data-derived profile shapes may allow a more accurate assessment of the effects of for example nutritional management or breeding system on progesterone...

  7. Elevated progesterone during ovarian stimulation for IVF

    DEFF Research Database (Denmark)

    Al-Azemi, M; Kyrou, D; Kolibianakis, E M

    2012-01-01

    There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also...... of premature progesterone in stimulated IVF cycles. There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular...... should document the cause and origin of premature progesterone in stimulated IVF cycles....

  8. Childhood conditions influence adult progesterone levels.

    Directory of Open Access Journals (Sweden)

    Alejandra Núñez-de la Mora

    2007-05-01

    Full Text Available Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among populations. The causes of such chronic differences are not well understood, but it has been hypothesised that they may result from varying tempos of growth and maturation and, by implication, from diverse environmental conditions encountered during childhood and adolescence.To test this hypothesis, we conducted a migrant study among first- and second-generation Bangladeshi women aged 19-39 who migrated to London, UK at different points in the life-course, women still resident in Bangladesh, and women of European descent living in neighbourhoods similar to those of the migrants in London (total n = 227. Data collected included saliva samples for radioimmunoassay of progesterone, anthropometrics, and information from questionnaires on diet, lifestyle, and health. Results from multiple linear regression, controlled for anthropometric and reproductive variables, show that women who spend their childhood in conditions of low energy expenditure, stable energy intake, good sanitation, low immune challenges, and good health care in the UK have up to 103% higher levels of salivary progesterone and an earlier maturation than women who develop in less optimal conditions in Sylhet, Bangladesh (F9,178 = 5.05, p < 0.001, standard error of the mean = 0.32; adjusted R(2 = 0.16. Our results point to the period prior to puberty as a sensitive phase when changes in environmental conditions positively impact developmental tempos such as menarcheal age (F2,81 = 3.21, p = 0.03 and patterns of ovarian function as measured using salivary progesterone (F2,81 = 3.14, p = 0.04.This research demonstrates that human females use an extended period of the life cycle prior

  9. Estrogen receptor, Progesterone receptor, HER2 status and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial

    DEFF Research Database (Denmark)

    Knoop, Ann S; Lænkholm, Anne-Vibeke; Jensen, Maj-Britt

    2014-01-01

    BACKGROUND: The DBCG 77C trial compared one year of tamoxifen in postmenopausal, steroid-receptor unknown, high-risk breast cancer patients to no adjuvant systemic therapy. After a potential follow-up of 30years we report overall efficacy of the study and results according to subtypes subsequentl...

  10. 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...

  11. 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.

  12. 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

  13. 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...

  14. CYP19 Genetic Polymorphism Haplotype AASA Is Associated with a Poor Prognosis in Premenopausal Women with Lymph Node-Negative, Hormone Receptor-Positive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sung-Hsin Kuo

    2013-01-01

    Full Text Available Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN- negative, hormone receptor- (HR- positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C, rs1065779 (A/C, CYP19 (TTTAn (short allele/long (S/L allele using the 7 TTTA repeat polymorphism as the cut-off, and rs1870050 (A/C was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS, disease-free survival (DFS, and overall survival (OS. Patients were divided into the 6 subhaplotypes of CCLA (41.1%, AASA (17.1%, CASA (11.9%, CCLC (8.9%, CCSA (7.5%, AASC (8.9%, and others (4.6%. In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR, 3.3; P=0.001, DFS (aHR, 2.5; P=0.0008, and OS (aHR, 2.9; P=0.0004 after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; P=0.0005, DFS (HR, 3.2; P=0.003, and OS (HR, 6.4; P=0.0009. However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; P=0.03 and OS (aHR, 4.4; P=0.01. Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Bastert Gunther

    2008-02-01

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

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

    DEFF Research Database (Denmark)

    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...

  3. 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.

  4. 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.

  5. 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

  6. Inhalation of progesterone inhibits chronic airway inflammation of mice exposed to ozone.

    Science.gov (United States)

    Fei, Xia; Bao, Wuping; Zhang, Pengyu; Zhang, Xue; Zhang, Guoqing; Zhang, Yingying; Zhou, Xin; Zhang, Min

    2017-05-01

    Chronic ozone exposure leads to a model of mice with lung inflammation, emphysema and oxidative stress. Progesterone plays an important role in attenuating the neuroinflammation. We assume that progesterone will reduce the chronic airway inflammation exposed to ozone and evaluate whether combination of progesterone with glucocorticoids results in synergistic effects. C57/BL6 mice were exposed to ozone (2.5ppm, 3h) 12 times over 6 weeks, and were administered with progesterone (0.03 or 0.3mg/L; inhaled) alone or combined with budesonide (BUD) (0.2g/L) after each exposure until the tenth week. Mice were studied 24h after final exposure, cells and inflammatory mediators were assessed in bronchoalveolar lavage fluid (BALF) and lungs used for evaluation of glucocorticoids receptors (GR), p38 mitogen-activated protein kinase (MAPK) phosphorylation and nuclear transcription factor κB (NF-κB) activation. Exposure to ozone resulted in a marked lung neutrophilia. Moreover, in ozone-exposed group, the levels of oxidative stress-related interleukin (IL)-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, airway inflammatory cells infiltration density, mean linear intercept (Lm) were greatly increased, FEV25 and glucocorticoids receptors (GR) were markedly decreased. Comparable to BUD, progesterone treatment dose-dependently led to a significant reduction of IL-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, and an increase of FEV25 and GR. Progesterone combined with BUD resulted in dramatic changes, compared to monotherapy of BUD or progesterone. Therefore, these results demonstrate that chronic ozone exposure has profound airway inflammatory effects counteracted by progesterone and progesterone acts synergistically with glucocorticoids in attenuating the airway inflammation dose-dependently. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. 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.

  8. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET)

    DEFF Research Database (Denmark)

    Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A

    2016-01-01

    breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were...... randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen...

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

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

    2016-01-01

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

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

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    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.

  11. Exploring the spatial dimension of estrogen and progesterone signaling: detection of nuclear labeling in lobular epithelial cells in normal mammary glands adjacent to breast cancer.

    Science.gov (United States)

    Grote, Anne; Abbas, Mahmoud; Linder, Nina; Kreipe, Hans H; Lundin, Johan; Feuerhake, Friedrich

    2014-01-01

    Comprehensive spatial assessment of hormone receptor immunohistochemistry staining in digital whole slide images of breast cancer requires accurate detection of positive nuclei within biologically relevant regions of interest. Herein, we propose a combination of automated region labeling at low resolution and subsequent detailed tissue evaluation of subcellular structures in lobular structures adjacent to breast cancer, as a proof of concept for the approach to analyze estrogen and progesterone receptor expression in the spatial context of surrounding tissue. Routinely processed paraffin sections of hormone receptor-negative ductal invasive breast cancer were stained for estrogen and progesterone receptor by immunohistochemistry. Digital whole slides were analyzed using commercially available image analysis software for advanced object-based analysis, applying textural, relational, and geometrical features. Mammary gland lobules were targeted as regions of interest for analysis at subcellular level in relation to their distance from coherent tumor as neighboring relevant tissue compartment. Lobule detection quality was evaluated visually by a pathologist. After rule set optimization in an estrogen receptor-stained training set, independent test sets (progesterone and estrogen receptor) showed acceptable detection quality in 33% of cases. Presence of disrupted lobular structures, either by brisk inflammatory infiltrate, or diffuse tumor infiltration, was common in cases with lower detection accuracy. Hormone receptor detection tended towards higher percentage of positively stained nuclei in lobules distant from the tumor border as compared to areas adjacent to the tumor. After adaptations of image analysis, corresponding evaluations were also feasible in hormone receptor positive breast cancer, with some limitations of automated separation of mammary epithelial cells from hormone receptor-positive tumor cells. As a proof of concept for object-oriented detection of

  12. Effects of metformin treatment on luteal phase progesterone concentration in polycystic ovary syndrome

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    Meenakumari K.J.

    2004-01-01

    Full Text Available The causes of luteal phase progesterone deficiency in polycystic ovary syndrome (PCOS are not known. To determine the possible involvement of hyperinsulinemia in luteal phase progesterone deficiency in women with PCOS, we examined the relationship between progesterone, luteinizing hormone (LH and insulin during the luteal phase and studied the effect of metformin on luteal progesterone levels in PCOS. Patients with PCOS (19 women aged 18-35 years were treated with metformin (500 mg three times daily for 4 weeks prior to the test cycle and throughout the study period, and submitted to ovulation induction with clomiphene citrate. Blood samples were collected from control (N = 5, same age range as PCOS women and PCOS women during the late follicular (one sample and luteal (3 samples phases and LH, insulin and progesterone concentrations were determined. Results were analyzed by one-way analysis of variance (ANOVA, Duncan's test and Karl Pearson's coefficient of correlation (r. The endocrine study showed low progesterone level (4.9 ng/ml during luteal phase in the PCOS women as compared with control (21.6 ng/ml. A significant negative correlation was observed between insulin and progesterone (r = -0.60; P < 0.01 and between progesterone and LH (r = -0.56; P < 0.05 concentrations, and a positive correlation (r = 0.83; P < 0.001 was observed between LH and insulin. The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml in PCOS women treated with metformin. The results suggest that hyperinsulinemia/insulin resistance may be responsible for low progesterone levels during the luteal phase in PCOS. The luteal progesterone level may be enhanced in PCOS by decreasing insulin secretion with metformin.

  13. 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.

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

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    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. Progesterone withdrawal. II: insensitivity to the sedative effects of a benzodiazepine.

    Science.gov (United States)

    Moran, M H; Goldberg, M; Smith, S S

    1998-10-05

    Previous results from this lab have demonstrated that the GABA-modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha, 5alpha-THP) exhibits withdrawal properties, increasing anxiety [M.A. Gallo, S.S. Smith, Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: a possible rat model of PMS anxiety, Pharmacol. Biochem. 46 (1993) 897-904.] and seizure susceptibility [S.S. Smith, Q.H. Gong, F.-C. Hsu, R.S. Markowitz, J. M.H. ffrench-Mullen, X. Li, GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.] upon abrupt discontinuation after chronic administration of its parent compound, progesterone (P), in a manner similar to other GABA-modulatory drugs. Further, we have demonstrated that withdrawal from P produces insensitivity to the potentiating effects of the benzodiazepine (BDZ) lorazepam (LZM) on GABA-gated Cl- current [A.-M.N. Costa, K.T. Spence, S.S. Smith, J.M. H. ffrench-Mullen, Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to BDZ modulation in rats CA1 hippocampus, J. Neurophysiology 74 (1995) 464-469; S.S. Smith, Q.H. Gong, F.-C. Hsu, R.S. Markowitz, J.M.H. ffrench-Mullen, X. Li, GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.], assessed using whole cell patch clamp procedures on pyramidal neurons acutely dissociated from CA1 hippocampus. The purpose of the present study was to examine the withdrawal effects of P on the sedative potency of LZM, tested behaviorally as the ability to maintain position on a variable speed treadmill following LZM administration (0.75 mg/kg). Both continuous (continuous release P capsule, single withdrawal) as well as discontinuous (multiple P injection, multiple withdrawal) paradigms were tested. Longer continuous release paradigms were more effective in abolishing the sedative effects of LZM

  16. Receptores de estrógeno e progesterona em células do sedimento de fluido peritoneal na endometriose pélvica: estudo imunocitoquímico Estrogen and progesterone receptors in peritoneal fluid cell sediment in pelvic endometriosis: immunocytochemical study

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    José Eleutério Junior

    2001-03-01

    Full Text Available Objetivo: avaliar a expressão de receptores de estrógeno (RE e progesterona (RP em esfregaços de sedimento de fluido peritoneal em pacientes com endometriose, comparando-a com a de mulheres sem endometriose. Métodos: foi realizado imunocitoquímica para RE e RP em esfregaços de sedimento de fluido peritoneal em 19 casos de endometriose e 7 sem endometriose (controle. Os dados foram submetidos ao teste t de Student para análise estatística. Resultados: em 84,6% dos casos de pacientes com endometriose, células tipo endometrial expressaram RE, numa média de 4,1%, ao passo que nos casos sem endometriose foi positivo em 42,9%, com uma expressão média de 4,5% (p = 0,1706. RP foi expresso apenas em um caso, com endometriose, com história de rotura de endometrioma. Conclusões: não houve diferença da expressão de RE entre os casos de endometriose e os casos-controle, observando-se um comportamento distinto em tecidos. Um mais aprofundado estudo deve ser feito para melhor avaliar o enigmático mecanismo envolvido na manifestação de receptores hormonais em células esfoliadas.Purpose: to evaluate the expression of estrogen (ER and progesterone (PR receptors in smears of peritoneal fluid sediment from patients with and without endometriosis. Methods: immunocytochemical study of ER and PR in smears of peritoneal fluid sediment in 19 cases with endometriosis and 7 without (control group, observing their expression. The data were submitted to Student's t-test to evaluate statistical significance. Results: in 84.6% of the cases with endometriosis, endometrial-like cells expressed ER (mean = 4.1%. In cases without endometriosis there was ER expression in 42.9%, with a mean of 4.5% (p = 0.1706. PR was expressed in only one case of endometriosis, with an endometrioma rupture history. Conclusions: there was no difference of ER expression between cases with endometriosis and the control group, in contrast to tissue behavior. Further cases must be

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

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    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

  18. Stress-induced increases in progesterone and cortisol in naturally cycling women

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    Alexandra Ycaza Herrera

    2016-06-01

    Full Text Available Studies with animals of both sexes show that the adrenal glands release progesterone in addition to cortisol in response to stress. However, little is known about the progesterone response to stress in naturally cycling women. We investigated the effect of stress on estradiol, progesterone, and cortisol levels in women during the follicular phase of the menstrual cycle. We found that physical stress (the cold pressor test had no effect on estradiol levels, but increased progesterone and cortisol. We also found positive correlations between baseline progesterone and cortisol levels, as well as between the change in progesterone and cortisol before and after water exposure in both the stress and control sessions. Mediation analyses revealed during the stress session, the change in progesterone from baseline to 42-min post-stress onset was mediated by the magnitude of change in cortisol levels across the same time span. Overall, these findings reveal that progesterone released in response to stress as observed in animals and men extends to women during the low ovarian output follicular phase of the menstrual cycle, and that the mechanism of release may be similar to the mechanism of cortisol release.

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

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    Keya De Mukhopadhyay

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

  20. Progesterone withdrawal I: pro-convulsant effects.

    Science.gov (United States)

    Moran, M H; Smith, S S

    1998-10-05

    Pro-convulsant withdrawal properties have been reported for a variety of GABA-modulatory drugs, such as the benzodiazepines (BDZs, [S.E. File, The history of BDZ dependence: a review of animal studies, Neurosci. Biobehav. Rev. 14 (1990) 135-146; P.R. Finley, P. E. Nolan, Precipitation of BDZ withdrawal following sudden discontinuation of midazolam, DICP 23 (1989) 151-152]), barbiturates and ethanol [N. Kokka, D.E. Sapp, U. Witte, R.W. Olsen, Sex differences in sensitivity to pentylenetetrazol but not in GABAA receptor binding, Pharm. Biochem. Behav. 43 (1992) 441-447]. In this report, we test the hypothesis that pro-convulsant effects are produced by withdrawal from the GABA-modulatory neurosteroid 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) after sustained exposure to elevated circulating levels of its parent compound progesterone (P). Seizure activity was precipitated by picrotoxin or with the BDZ inverse agonist n-methyl-beta-carboline-3-carboxamide (beta-CC), and a seizure rating determined 24 h after abrupt discontinuation of P following a multiple withdrawal/chronic administration paradigm. In some cases, a pseudopregnant rat model was employed to produce increased ovarian production of P prior to withdrawal (ovariectomy). Rats undergoing P withdrawal exhibited greater seizure-like activity than vehicle-treated controls, and received seizure scores in the same range as rats undergoing BDZ withdrawal. Administration of a 5alpha-reductase blocker, MK-906, along with P, prevented this pro-convulsant effect of P withdrawal, suggesting that the GABA-modulatory 3alpha,5alpha-THP is the active compound responsible for this withdrawal effect. Combined administration of P and diazepam produced synergistic effects upon withdrawal and produced a seizure score higher than observed after withdrawal from either agent alone. These results suggest that P exhibits withdrawal properties via the neuroactive steroid 3alpha, 5alpha-THP, that include exacerbation of

  1. 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.

  2. The 11alpha and 17alpha-progesterone hydroxylases of Rhizopus nigricans NRRL 1477.

    Science.gov (United States)

    Allam, A M; el-Kady, I A

    1975-01-01

    Differential induction of cultures of Rhizopus nigricans indicated that hydroxylation of progesterone at the 11alpha- and 17alpha-positions is due to two separate enzymes. This is supported by the finding that 11alpha- and 17alpha-hydroxylating activities are separated by differential centrigufation of cell-free extracts. The feasibility of introducing a hydroxyl group at the 11alpha- or 17alpha-position of hydroxylated progesterone derivatives was tested.

  3. 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.

  4. A single glycine-alanine exchange directs ligand specificity of the elephant progestin receptor.

    Directory of Open Access Journals (Sweden)

    Michael Wierer

    Full Text Available The primary gestagen of elephants is 5α-dihydroprogesterone (DHP, which is unlike all other mammals studied until now. The level of DHP in elephants equals that of progesterone in other mammals, and elephants are able to bind DHP with similar affinity to progesterone indicating a unique ligand-binding specificity of the elephant progestin receptor (PR. Using site-directed mutagenesis in combination with in vitro binding studies we here report that this change in specificity is due to a single glycine to alanine exchange at position 722 (G722A of PR, which specifically increases DHP affinity while not affecting binding of progesterone. By conducting molecular dynamics simulations comparing human and elephant PR ligand-binding domains (LBD, we observed that the alanine methyl group at position 722 is able to push the DHP A-ring into a position similar to progesterone. In the human PR, the DHP A-ring position is twisted towards helix 3 of PR thereby disturbing the hydrogen bond pattern around the C3-keto group, resulting in a lower binding affinity. Furthermore, we observed that the elephant PR ligand-binding pocket is more rigid than the human analogue, which probably explains the higher affinity towards both progesterone and DHP. Interestingly, the G722A substitution is not elephant-specific, rather it is also present in five independent lineages of mammalian evolution, suggesting a special role of the substitution for the development of distinct mammalian gestagen systems.

  5. Bioavailability and Fate of Sediment-Associated Progesterone in Aquatic Systems.

    Science.gov (United States)

    Sangster, Jodi L; Ali, Jonathan M; Snow, Daniel D; Kolok, Alan S; Bartelt-Hunt, Shannon L

    2016-04-05

    The environmental fate and bioavailability of progesterone, a steroid hormone known to cause endocrine-disrupting effects in aquatic organisms, is of growing concern due to its occurrence in the environment in water and sediment influenced by wastewater treatment plant and paper mill effluents, as well as livestock production. The objective of this study was to evaluate the fate of progesterone in two natural sediments and the corresponding alteration of gene expression in three steroid-responsive genes; vitellogenin, androgen receptor and estrogen receptor alpha. When exposed to progesterone-spiked sand, fathead minnows (Pimephales promelas) exhibited significant reductions in the expression of vitellogenin and androgen receptor expression. In contrast, fish exposed to progesterone associated with the silty loam sediment did not show a biological response at 7 days and only realized a significant reduction in vitellogenin. In both sediments, progesterone degradation resulted in the production of androgens including androsteinedione, testosterone, and androstadienedione, as well as the antiestrogen, testolactone. Differences in compound fate resulted in organism exposure to different suites of metabolites either in water or associated with the sediment. Results from this study suggest that environmental progestagens will lead to defeminization at environmentally relevant concentrations, and that exposure is influenced by sediment properties.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. Artificial induction of lactation in ewes: the involvement of progesterone and prolactin in lactogenesis.

    Science.gov (United States)

    Fulkerson, W J; Hooley, R D; McDowell, G H; Fell, L R

    1976-10-01

    An attempt has been made to evaluate the importance of prolactin and 'progesterone withdrawal' for lactogenesis. The experimental model system used was the ovariectomized, non-pregnant ewe induced to lactate artifically by treatment with trigger hormone (either oestrogen, glucocorticoid or oxytocin) alone or in combination with progesterone. It appears from the results that prolactin is important in the lactogenic responses elicited by oestrogen and oxytocin but not as important in the response elicited by glucocorticoid. Moreover, the results suggest that, in the ewe, an appropriate positive hormonal stimulus will overcome the inhibitory influence of progesterone on lactogenesis.

  12. Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies

    DEFF Research Database (Denmark)

    Rode, Line; Langhoff-Roos, Jens; Andersson, Charlotte

    2009-01-01

    of preterm delivery in women with preterm labor. CONCLUSIONS: In women with a singleton pregnancy and previous preterm delivery, progesterone reduces the rates of preterm delivery before 32 weeks, perinatal death, as well as respiratory distress syndrome and necrotizing enterocolitis in the newborn. Women...... now showed that progesterone supplementation was associated with a significant reduction of delivery before 32 weeks and of perinatal mortality. Furthermore, a third trial showed a positive effect on women with a short cervix at 23 weeks, and a fourth study showed that progesterone reduces the risk...

  13. 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.

  14. 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.

  15. 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

  16. 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...

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

    Directory of Open Access Journals (Sweden)

    Cory A. Rubel

    2016-10-01

    Full Text Available Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2 are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of the Pgr gene but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer-related molecular profile in a progesterone-independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mice based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage.

  2. 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.

  3. In situ detection of progesterone binding sites in the plasma membrane of the filamentous fungus Rhizopus nigricans: In situ detekcija vezavnih mest za progesteron v plazemski membrani filamentozne glive Rhizopus nigricans:

    OpenAIRE

    Breskvar, Katja; Jeraj, Nataša; LENASI, HELENA; Romih, Rok

    2003-01-01

    Steroid hydroxylating enzymes in the fungus Rhizopus nigricans are induced by progesterone and by some other steroids. It is known that in higher organisms steroids exert their nongenomic action via steroid binding proteins located inthe plasma membrane of the cells, thus our aim was to detect progesterone binding sites in R. nigricans plasma membrane. In this report membrane receptors were identified by two independent methods, analysis of progesteronebinding to plasma membrane fraction by c...

  4. [Progesterone and prevention of preterm birth].

    Science.gov (United States)

    Fuchs, F; Senat, M-V

    2015-10-01

    The literature confirms the interest of progesterone for prevention of preterm delivery in specific indications for patients carrying a singleton pregnancy. In contrast, randomized trials have shown no benefit using progesterone in the prevention of prematurity in twins and even an adverse effect. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. PROGESTERONE: BIOSYNTHESIS FROM PREGNENOLONE IN HOLARRHENA FLORIBUNDA.

    Science.gov (United States)

    BENNETT, R D; HEFTMANN, E

    1965-08-06

    After administration of pregnenolone-4-C(14) to Holarrhena floribunda leaves, radioactive progesterone was isolated and purified to constant specific activity by chromatography, conversion to a derivative, and recrystallization. The result suggests that the biogenetic sequence leading to progesterone is the same in plants as in animals.

  6. 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

  7. Autoimmune Progesterone Dermatitis: A Case Report

    Directory of Open Access Journals (Sweden)

    Rachana George

    2012-01-01

    Full Text Available Background. Autoimmune progesterone dermatitis is a rare cyclic premenstrual allergic reaction to progesterone produced during the luteal phase of a woman's menstrual cycle. Patients present with a variety of conditions including erythema multiforme, eczema, urticaria, angioedema, and progesterone-induced anaphylaxis. Case. Thirty-eight-year-old woman G2P2002 presents with erythema multiforme and urticarial rash one week prior to her menses starting one year after menarche. She was treated with oral contraceptive pills and the symptoms resolved. Conclusion. This is a typical case of progesterone autoimmunity. The diagnosis is based on cyclic nature of the dermatitis. This differentiates the condition from other allergies or systemic diseases with skin manifestations. Inhibition of ovulation in such cases results in decrease in progesterone secretion and prevention of symptoms.

  8. 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.

  9. 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.

  10. 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...

  11. Aldosterone and progesterone-secreting adrenocortical adenocarcinoma in a cat with a concurrent meningioma

    Directory of Open Access Journals (Sweden)

    Jana Leshinsky

    2016-01-01

    Full Text Available Case summary A 12-year-old, male neutered domestic shorthair cat was referred for investigation of suspected hyperaldosteronism due to persistent hypokalaemia, hindlimb ataxia, weakness of 1 month’s duration and a left adrenal mass that was detected on abdominal ultrasound. Neurological examination findings at referral were suggestive of a concurrent left forebrain lesion. Hyperaldosteronism and concurrent hyperprogesteronism were confirmed on endocrine testing. On computed tomography (CT of the abdomen and thorax there was no evidence of local vascular invasion by the adrenal mass or of metastatic disease. CT and magnetic resonance imaging featured a large, focal rim-enhancing extra-axial left forebrain lesion consistent with a meningioma. Surgical excision of the forebrain mass was followed by adrenalectomy 2 weeks later. The tumours were classified on histopathology as a psammomatous meningioma and an adrenocortical adenocarcinoma, respectively. Immunohistochemical staining of the meningioma confirmed the presence of progesterone receptors. The cat remains well 2 years later. Relevance and novel information In humans, elevated serum progesterone levels have been associated with rapid growth of meningiomas due to the presence of progesterone receptors on the tumour. This is the first report of a cat with a progesterone and aldosterone-secreting adrenocortical adenocarcinoma and a concurrent meningioma. Clinicians should be aware of the potential effect of elevated progesterone on meningiomas in cats.

  12. Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone.

    Science.gov (United States)

    Miller, Melissa R; Mannowetz, Nadja; Iavarone, Anthony T; Safavi, Rojin; Gracheva, Elena O; Smith, James F; Hill, Rose Z; Bautista, Diana M; Kirichok, Yuriy; Lishko, Polina V

    2016-04-29

    Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/β hydrolase domain-containing protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization. Copyright © 2016, American Association for the Advancement of Science.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. The breast cancer hormone receptor retesting controversy in Newfoundland and Labrador, Canada: lessons for the health system.

    Science.gov (United States)

    Gregory, Deborah M; Parfrey, Patrick S

    2010-01-01

    The treatment of newly diagnosed breast cancer patients with hormonal treatment is determined by the presence of estrogen receptor and progesterone receptor status in breast cancer. In Newfoundland and Labrador (NL), 425 of 1088 (39.1%) patients who had original "negative" receptor tests conducted between 1997 and 2005, had positive results upon retesting in a specialized laboratory. This commentary addresses (1) the diagnostic utility of estrogen and progesterone testing for breast cancer in general, (2) specific testing problems that occurred in NL, (3) scientific problems associated with retesting, and (4) the impact on public trust and the resulting legal and political responses that occurred as a result of the adverse events associated with false-negative hormone receptor tests. Finally, the lessons learned will be discussed including known high false-negative rates associated with the tests and the bias associated with retesting, the need for quality assurance and national standards, public education, and appropriate communication with patients and the public.

  1. 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...

  2. 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...

  3. 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,

  4. 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

  5. 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...

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. In-vitro rescue and recovery studies of human melanoma (BLM) cell growth, adhesion and migration functions after treatment with progesterone.

    Science.gov (United States)

    Leder, Douglas C; Brown, Jason R; Ramaraj, Pandurangan

    2015-01-01

    Treatment of human melanoma (BLM) cells for 48 hrs with progesterone resulted in a significant inhibition of cell growth. The mechanism of growth inhibition was due to autophagy and this action of progesterone was not mediated through progesterone receptor. As cells were floating during treatment, adhesion assay was performed, which showed complete loss of adhesion. When cells were allowed to recover after treatment by culturing in growth medium without progesterone, there was recovery in cell growth. Preliminary experiments on adhesion and recovery cell growth prompted us to suppress autophagic lysosomal degradation with 3-methyladenine (3-MA), which resulted in partial rescue of cell growth, adhesion and migration functions. The above experimental design gave rise to two experimental groups viz., progesterone treated and 3-MA rescued. Since, recovery studies also showed improvement in cell growth, progesterone treated and 3-MA rescued groups were allowed to recover on their own for first 48 hrs and then a second 48 hrs. Comparison of in-vitro cell growth, adhesion and migration functions of progesterone treated, 3-MA rescued and recovered human melanoma cells revealed that the recovery of 3-MA rescued cells was better than the recovery of progesterone treated cells in terms of cell growth and adhesion functions. These in-vitro experiments not only provided the scientific basis for epidemiological findings that menstruating females were better protected in melanoma, but also showed the potential of progesterone to act as an anti-cancer agent for melanoma treatment.

  13. Sensor and instrumentation for progesterone detection

    KAUST Repository

    Zia, Asif I.

    2012-05-01

    The reported research work uses a real time and noninvasive method to detect progesterone hormone concentration in purified water using Electrochemical Impedance Spectroscopy (E.I.S.) technique. Planar capacitive sensor, consisting of inter-digitated microelectrodes, is designed and fabricated on silicon substrate using thin-film Microelectromechanical system (MEMS) based semiconductor device fabrication technology. The sensor in conjunction with EIS is used to evaluate conductivity, permeability and dielectric properties of reproductive hormone progesterone and its concentration quantification in purified water. Impedance spectrums are obtained with various concentrations of the hormone in purified water by using an electric circuit in order to extract sample conductance. Relationship of sample conductance with progesterone concentration level is studied in this research work. The ability of E.I.S. to detect progesterone concentration is aimed to be used in dairy farming industry in order to obtain better reproductive performance of the dairy cattle. © 2012 IEEE.

  14. Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells.

    Science.gov (United States)

    Li, Mei; Zhao, Dan; Ma, Gui; Zhang, Baotong; Fu, Xiaoying; Zhu, Zhengmao; Fu, Liya; Sun, Xiaodong; Dong, Jin-Tang

    2013-01-04

    Progesterone (Pg) is an essential steroid hormone during mammary gland development and tumorigenesis, including the maintenance of epithelial stem/progenitor cells. Pg functions through interaction with the progesterone receptors (PR) and Pg-PR signaling is thought to be mediated by key transcription factors, which are largely unidentified. In this study, we have identified the ATBF1 transcription factor as a transcriptional target of Pg-PR signaling in mammary epithelial cells. Pg treatment dramatically increased ATBF1 expression at both mRNA and protein levels in cultured cells and mammary tissues. As expected, the induction of ATBF1 was PR-dependent, as it only occurred in PR-positive but not in PR-negative cells, and pretreatment with the Pg antagonist RU-486 or RNAi-mediated knockdown of PR abolished the upregulation of ATBF1 by Pg. Promoter-reporter and ChIP assays further showed that Pg-activated PR directly binds to the ATBF1 promoter to induce its transcription. Prevention of ATBF1 induction inhibited the function of Pg in promoting progenitor cell transition, as indicated by colony formation in a Matrigel culture assay and expression of stem cell markers CD49f and CD44. These findings suggest that ATBF1 plays a crucial role in the Pg-PR signaling pathway in mammary epithelial cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. WISP-2 gene in human breast cancer: estrogen and progesterone inducible expression and regulation of tumor cell proliferation.

    Science.gov (United States)

    Banerjee, Snigdha; Saxena, Neela; Sengupta, Krishanu; Tawfik, Ossama; Mayo, Matthew S; Banerjee, Sushanta K

    2003-01-01

    WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER) positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780). Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17beta-estradiol by upregulating the WISP-2 gene after transfection with ER-alpha, providing further evidences that WISP-2 expression is mediated through ER-alpha. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation.

  16. WISP-2 Gene in Human Breast Cancer: Estrogen and Progesterone Inducible Expression and Regulation of Tumor Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Snigdha Banerjee

    2003-01-01

    Full Text Available WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780. Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17β-estradiol by upregulating the WISP-2 gene after transfection with ER-α, providing further evidences that WISP-2 expression is mediated through ER-α. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation.

  17. WISP-2 Gene in Human Breast Cancer: Estrogen and Progesterone Inducible Expression and Regulation of Tumor Cell Proliferation1

    Science.gov (United States)

    Banerjee, Snigdha; Saxena, Neela; Sengupta, Krishanu; Tawfik, Ossama; Mayo, Matthew S; Banerjee, Sushanta K

    2003-01-01

    Abstract WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER) positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780). Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17β-estradiol by upregulating the WISP-2 gene after transfection with ER-α, providing further evidences that WISP-2 expression is mediated through ER-α. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation. PMID:12659671

  18. Progesterone withdrawal effects in the open field test can be predicted by elevated plus maze performance.

    Science.gov (United States)

    Löfgren, Magnus; Johansson, Inga-Maj; Meyerson, Bengt; Lundgren, Per; Bäckström, Torbjörn

    2006-08-01

    Allopregnanolone (3alpha-hydroxy-5alpha-pregnane-20-one) is a ring-A-reduced metabolite of progesterone, which is naturally produced during the luteal phase of the menstrual cycle, during pregnancy and by stressful events. The steroid hormone inhibits neural functions through increased chloride ion flux through the GABA(A) receptor. The effects and subsequent withdrawal symptoms are similar to those caused by alcohol, benzodiazepines and barbiturates. This study examined the withdrawal effects of progesterone with regards to the influence of individual baseline exploration and risk taking. Rats were tested on the elevated plus maze (EPM) before hormonal treatment, in order to evaluate differences in risk taking and exploration of open and elevated areas. Treatment consisted of ten consecutive once a day progesterone or vehicle s.c. injections. On the last day of treatment, estradiol was injected in addition to progesterone, followed by a 24-h withdrawal before testing in the open field test (OF). Progesterone-treated rats showed a withdrawal effect of open area avoidance in the OF. The vehicle-treated control rats showed strong correlations between the EPM and OF parameters. This relationship was not found for the progesterone group at withdrawal. Rats with greater numbers of open arm entrance in the EPM pretest showed an increased sensitivity to progesterone withdrawal (PWD) compared to rats with low exploration and risk taking. The results indicate that the effects of PWD relate to individual exploration and risk taking. Furthermore, the possible analogy of PWD and PMS/PMDD in relation to individual traits is discussed.

  19. 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.

  20. The impact of progesterone on memory consolidation of threatening images in women.

    Science.gov (United States)

    Felmingham, Kim L; Fong, Wing Chee; Bryant, Richard A

    2012-11-01

    Recent findings suggest that consolidation of emotional memories is influenced by menstrual phase in women. In contrast to other phases, in the mid-luteal phase when progesterone levels are elevated, cortisol levels are increased and correlated with emotional memory. This study examined the impact of progesterone on cortisol and memory consolidation of threatening stimuli under stressful conditions. Thirty women were recruited for the high progesterone group (in the mid-luteal phase) and 26 for the low progesterone group (in non-luteal phases of the menstrual cycle). Women were shown a series of 20 neutral or threatening images followed immediately by either a stressor (cold pressor task) or control condition. Participants returned two days later for a surprise free recall test of the images and salivary cortisol responses were monitored. High progesterone levels were associated with higher baseline and stress-evoked cortisol levels, and enhanced memory of negative images when stress was received. A positive correlation was found between stress-induced cortisol levels and memory recall of threatening images. These findings suggest that progesterone mediates cortisol responses to stress and subsequently predicts memory recall for emotionally arousing stimuli. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Chun-E Ren

    2015-03-01

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

  2. PROGESTERONE EXERTS NEUROPROTECTIVE EFFECTS AFTER BRAIN INJURY

    OpenAIRE

    Stein, Donald G.

    2007-01-01

    Progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. This review assesses recent, primarily in vivo, evidence that progesterone can play an important role in promoting and enhancing repair after traumatic brain injury and stroke. Although many of its specific actions on neuroplasticity remain to be discovered, there is growing evidence that this hormone may be a safe and effective treatment for traumatic...

  3. Progesterone exerts neuroprotective effects after brain injury.

    Science.gov (United States)

    Stein, Donald G

    2008-03-01

    Progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. This review assesses recent, primarily in vivo, evidence that progesterone can play an important role in promoting and enhancing repair after traumatic brain injury and stroke. Although many of its specific actions on neuroplasticity remain to be discovered, there is growing evidence that this hormone may be a safe and effective treatment for traumatic brain injury and other neural disorders in humans.

  4. 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

  5. Progesterone modulates microtubule dynamics and epiboly progression during zebrafish gastrulation.

    Science.gov (United States)

    Eckerle, Stephanie; Ringler, Mario; Lecaudey, Virginie; Nitschke, Roland; Driever, Wolfgang

    2017-12-26

    Control of microtubule dynamics is crucial for cell migration. We analyzed regulation of microtubule network dynamics in the zebrafish yolk cell during epiboly, the earliest coordinated gastrulation movement. We labeled microtubules with EMTB-3GFP and EB3-mCherry to visualize and measure microtubule dynamics by TIRF microscopy live imaging. Yolk cell microtubules dynamics is temporally modulated during epiboly progression. We used maternal zygotic Pou5f3 mutant (MZspg) embryos, which develop strong distortions of microtubule network organization and epiboly retardation, to investigate genetic control of microtubule dynamics. In MZspg embryos, microtubule plus-end growth tracks move slower and are less straight compared to wild-type. MZspg embryos have altered steroidogenic enzyme expression, resulting in increased pregnenolone and reduced progesterone levels. We show that progesterone positively affects microtubule plus-end growth and track straightness. Progesterone may thus act as a non-cell-autonomous regulator of microtubule dynamics across the large yolk cell, and may adjust differing demands on microtubule dynamics and stability during initiation and progression phases of epiboly. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women.

    Science.gov (United States)

    Milivojevic, Verica; Fox, Helen C; Sofuoglu, Mehmet; Covault, Jonathan; Sinha, Rajita

    2016-03-01

    Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5-7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine

  7. 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.

  8. 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.

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

    Science.gov (United States)

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

    2016-06-10

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

  10. 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.

  11. 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

  12. 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

  13. Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal mammary gland in a murine model.

    Science.gov (United States)

    Raafat, A M; Hofseth, L J; Haslam, S Z

    2001-02-01

    The aim of the study was to analyze the proliferative response of the normal mammary gland to combination hormone replacement therapy with estrogen and progesterone in a murine model of early versus late postmenopausal states. Ovariectomized mice were injected daily for up to 56 days with estrogen plus progesterone, starting at either 1 or 5 weeks after ovariectomy to simulate early and late menopausal periods, respectively. At various times after treatment, proliferation was analyzed by deoxyribonucleic acid histoautoradiography and whole-mount preparations. The induction of progesterone receptor by estrogen was also analyzed. To distinguish between estrogen- and progesterone-specific responses, we tested the effects of the antiprogesterone mifepristone (RU 486) and the antiestrogen ICI 182,780. The acute response to estrogen-progesterone therapy in the early postmenopausal period resulted in duct-end enlargement, ductal side branching, alveolar bud formation, and a 100-fold increase in epithelial cell proliferation. This was caused by the dominant effect of progesterone acting through the progesterone receptor. In the late postmenopausal period the acute response produced only duct-end enlargement; the 100-fold increase in epithelial cell proliferation resulted from the dominant effect of estrogen. After long-term treatment, both early and late postmenopausal glands exhibited similar morphologic features and a 9-fold higher steady-state proliferation rate than was found in control-treated groups. Starting combined estrogen and progesterone hormone replacement therapy in either early or late postmenopause produced a persistent, steady-state 9-fold increase in epithelial cell proliferation, which could be a contributing factor to increased breast cancer risk. The acute response in the late postmenopausal period mimics the hormonal response of the pubertal mammary gland, which in rodents is the stage most susceptible to carcinogen-induced mammary tumorigenesis

  14. 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.

  15. 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 ...

  16. 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

  17. Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

    OpenAIRE

    Smith, Sheryl S.; Shen, Hui; Gong, Qi Hua; Zhou, Xiangping

    2007-01-01

    Neurosteroids, such as the progesterone metabolite 3α-OH-5α[β]-pregnan-20-one (THP or [allo]pregnanolone), function as potent positive modulators of the GABAA receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sus...

  18. Hormone-receptor expression and ovarian cancer survival

    DEFF Research Database (Denmark)

    Sieh, Weiva; Köbel, Martin; Longacre, Teri A

    2013-01-01

    Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated...

  19. 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...

  20. Respiratory responses to progesterone and allopregnanolone following chronic caffeine treatment in newborn female rats.

    Science.gov (United States)

    Uppari, Naga Praveena; Joseph, Vincent; Bairam, Aida

    2017-06-01

    We recently showed that in 12-day-old male rats exposed to caffeine for 10 consecutive days, progesterone inhibits the respiratory response to hypoxia and increases apnea frequency (Uppari et al., 2016). This was partly due to a higher inhibitory response of GABAa receptor to allopregnanolone, the neuroactive metabolite of progesterone. In the present study, we addressed whether similar effects occur in females. We used newborn female rats daily gavaged with water (control) or caffeine (15mg/kg) between the postnatal (P) days 3-12. At P12, we recorded ventilation, metabolic rate, and apnea frequency and duration in normoxia and in response to moderate hypoxia, following an intraperitonial injection of progesterone (4mg/kg) or allopregnanolone (10mg/kg). In control rats, progesterone had no effect on breathing in normoxia and in hypoxia, and in rats treated with caffeine it decreased the initial increase in respiratory frequency in hypoxia. In both groups, allopregnalone decreased breathing frequency in normoxia and in hypoxia and increased the frequency of apnea in normoxia in control rats and in rats treated with caffeine. Injection of bicuculline (a specific GABAa receptor antagonist) prevented the inhibitory effects of allopregnanolone on breathing in both groups. These data indicate that chronic caffeine treatment unmasked an inhibitory effect of progesterone on the hypoxic response but this was weaker than in males, and contrasting to what was observed in male rats (Uppari et al., 2016), GABAa receptors are not significantly affected by chronic caffeine treatment in newborn female rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. 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

  2. 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.

  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.

    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.

  4. Comparative evaluation of ovarian structures in cattle by palpation per rectum, ultrasonography and plasma progesterone concentration.

    Science.gov (United States)

    Ribadu, A Y; Ward, W R; Dobson, H

    1994-11-05

    The aims of this study were to determine the relationship between the ultrasonographic determination of corpora lutea and the plasma progesterone profile of cyclic cows during an oestrous cycle, and to compare the accuracy of detection of normal and abnormal ovarian structures by ultrasonography and palpation per rectum, based on the plasma progesterone profile. The ovaries of six lactating cyclic dairy cows were scanned and blood samples were obtained three times a week for one month. There was a high correlation (r = 0.85) between the diameter of the corpus luteum and the plasma progesterone concentration, but on days -3 and -2 (oestrus = day 0) the diameter was the same as mid-luteal values but it was functionally inactive (plasma progesterone cows by using the plasma progesterone concentration and the dissection of ovaries post mortem as standards. The sensitivity, specificity and positive predictive value of palpation for identifying mid-cyclic corpora lutea were 85 per cent, 95.7 per cent and 89.5 per cent, respectively. Ultrasonography had a sensitivity of 95 per cent, a specificity of 100 per cent and a positive predictive value of 100 per cent. Twenty-nine cows were diagnosed by palpation per rectum as having either follicular or luteal cysts. During ultrasonography, an ovarian cyst was defined as a non-echogenic structure at least 5 mm in diameter.(ABSTRACT TRUNCATED AT 250 WORDS)

  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. 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.

  9. The role of gamma/delta T cells in progesterone-mediated immunomodulation during pregnancy: a review.

    Science.gov (United States)

    Szekeres-Bartho, J; Barakonyi, A; Polgar, B; Par, G; Faust, Z; Palkovics, T; Szereday, L

    1999-07-01

    To determine if pregnancy is recognized by the immune system and if inadequate recognition of fetal antigens might result in failed pregnancy. Review of literature and current data. In the decidua gamma/delta TCR positive cells significantly increase in number. A subset of gamma/delta T cells reacts with nonpolymorphic Class I or Class I like molecules. Trophoblast recognition is mediated by the V gamma 1 subset which recognize a conserved mammalian sequence on the trophoblast. Almost all gamma/delta T cells in the decidua are activated and use the V delta 1 chain, whereas the majority of human peripheral gamma/delta lymphocytes expresses V gamma 9/V delta 2 TCR. Peripheral gamma/delta T cells of healthy pregnant women preferentially use V gamma V delta 1 chains, on the other hand, those of recurrent aborters use the V gamma 9V delta 2 combination. Signaling via the V gamma 1.4V delta 1 receptor induces a Th2 type response, whereas activation of the lymphocytes via the V gamma 9V delta 2 receptor results in increased IL-12 production and natural killer (NK) activity. In the presence of progesterone, activated lymphocytes synthesize the progesterone induced blocking factor (PIBF), which inhibits NK activity and exerts an anti abortive effect in vivo. Decidual CD56+ and gamma delta+ cells are to a high extent the same population. All decidual CD56+ cells express PIBF, thus it cannot be excluded that local production of this substance contributes to low decidual NK activity and thus to the success of the pregnancy.

  10. 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....

  11. 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.

  12. 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.

  13. 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

  14. Progesterone and non-specific immunologic mechanisms in pregnancy.

    Science.gov (United States)

    Szekeres-Bartho, J; Par, G; Szereday, L; Smart, C Y; Achatz, I

    1997-09-01

    Progesterone-dependent immunomodulation is one of the mechanisms that enables pregnancy to proceed to term. Immunologic effects of progesterone are mediated by a protein named the progesterone-induced blocking factor (PIBF). Among other effects this protein inhibits natural killer (NK) activity and displays an anti-abortive effect in mice. Recently, we have shown that PIBF induces a Th2 shift in vitro. The present study was aimed at investigating the in vivo effect of PIBF on cytokine production, as well as the relationship between cytokine production, NK activity, and pregnancy loss. Balb-c mice on day 8.5 of pregnancy were injected intraperitoneally with 0.5 mg of rabbit anti-PIBF immunoglobulin G (IgG). Another group of mice was simultaneously treated with anti-NK monoclonal antibodies. Mice treated with the same amount of normal rabbit serum or untreated mice of similar gestational age were used as controls. The animals were sacrificed and their uteri were inspected. The ratio of living and resorbed embryos was determined. NK activity as well as cytokine expression on the spleen cells were determined by immunocytochemistry and enzyme-linked immunoadsorbent assay (ELISA). Mitogen-activated spleen cells from anti-PIBF-treated mice produced significantly (P < 0.001) less IL-10 than those of pregnant control mice. A significantly higher percentage (P < 0.001) of spleen cells from anti-PIBF-treated mice expressed interferon-gamma (IFN gamma) as determined by immunocytochemistry, than those of untreated pregnant mice. There was a positive relationship between the percentage of IFN gamma-positive spleen cells and resorption rates, and an inverse relationship between the latter and interleukin-10 (IL-10) production. All these effects were corrected by treatment with anti-NK antibodies. Our data suggest that PIBF contributes to the success of gestation via cytokine-mediated inhibition of NK activity.

  15. Establishment and characterization of two human breast carcinoma cell lines by spontaneous immortalization: Discordance between Estrogen, Progesterone and HER2/neu receptors of breast carcinoma tissues with derived cell lines

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    Kamalidehghan Behnam

    2012-10-01

    Full Text Available Abstract Background Breast cancer is one of the most common cancers among women throughout the world. Therefore, established cell lines are widely used as in vitro experimental models in cancer research. Methods Two continuous human breast cell lines, designated MBC1 and MBC2, were successfully established and characterized from invasive ductal breast carcinoma tissues of Malaysian patients. MBC1 and MBC2 have been characterized in terms of morphology analysis, population doubling time, clonogenic formation, wound healing assay, invasion assay, cell cycle, DNA profiling, fluorescence immunocytochemistry, Western blotting and karyotyping. Results MBC1 and MBC2 exhibited adherent monolayer epithelial morphology at a passage number of 150. Receptor status of MBC1 and MBC2 show (ER+, PR+, HER2+ and (ER+, PR-, HER2+, respectively. These results are in discordance with histopathological studies of the tumoral tissues, which were triple negative and (ER-, PR-, HER2+ for MBC1 and MBC2, respectively. Both cell lines were capable of growing in soft agar culture, which suggests their metastatic potential. The MBC1 and MBC2 metaphase spreads showed an abnormal karyotype, including hyperdiploidy and complex rearrangements with modes of 52–58 chromosomes per cell. Conclusions Loss or gain in secondary properties, deregulation and specific genetic changes possibly conferred receptor changes during the culturing of tumoral cells. Thus, we hypothesize that, among heterogenous tumoral cells, only a small minority of ER+/PR+/HER2+ and ER+/PR-/HER2+ cells with lower energy metabolism might survive and adjust easily to in vitro conditions. These cell lines will pave the way for new perspectives in genetic and biological investigations, drug resistance and chemotherapy studies, and would serve as prototype models in Malaysian breast carcinogenesis investigations.

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

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    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

  17. Neurosteroids and GABA-A receptor function

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    Mingde eWang

    2011-10-01

    Full Text Available Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one, 5α-androstane-3α, 17α-diol (Adiol and 3α5α-tetrahydrodeoxy-corticosterone (3α5α-THDOC enhance the GABA mediated Cl− currents acting on a site (or sites distinct from the GABA, benzodiazepine, barbiturate and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABAA-receptor function and activate delta-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnanesteroids and pregnenolone sulfate (PS are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA receptor, mood changes and cognitive functions.

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

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    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.

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

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    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.

  20. 99mTc-EDDA/HYNIC-TOC in management of patients with head and neck somatostatin receptor positive tumors.

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    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