239 results on '"Ambs S"'
Search Results
2. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis
- Author
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Crawford, NPS, Qian, X, Ziogas, A, Papageorge, AG, Boersma, BJ, Walker, RC, Lukes, L, Rowe, WL, Zhang, J, Ambs, S, Lowy, DR, Anton-Culver, H, and Hunter, KW
- Subjects
Genetics ,Developmental Biology - Abstract
A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.
- Published
- 2007
3. A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis
- Author
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Subramanian, M, Francis, P, Bilke, S, Li, X L, Hara, T, Lu, X, Jones, M F, Walker, R L, Zhu, Y, Pineda, M, Lee, C, Varanasi, L, Yang, Y, Martinez, L A, Luo, J, Ambs, S, Sharma, S, Wakefield, L M, Meltzer, P S, and Lal, A
- Published
- 2015
- Full Text
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4. The Role of Nongenotoxic Mechanisms in Arylamine Carcinogenesis
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Ambs, S. and Bitsch, A.
- Published
- 1994
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5. MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer
- Author
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Hudson, R S, Yi, M, Esposito, D, Glynn, S A, Starks, A M, Yang, Y, Schetter, A J, Watkins, S K, Hurwitz, A A, Dorsey, T H, Stephens, R M, Croce, C M, and Ambs, S
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- 2013
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6. Constitutive expression of inducible nitric oxide synthase in human bronchial epithelial cells induces c-fos and stimulates the cGMP pathway.
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Felley-Bosco, E, Ambs, S, Lowenstein, C J, Keefer, L K, and Harris, C C
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- 1994
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7. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
- Author
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Ng, MCY, Graff, M, Lu, Y, Justice, AE, Mudgal, P, Liu, CT, Young, K, Yanek, LR, Feitosa, MF, Wojczynski, MK, Rand, K, Brody, JA, Cade, BE, Dimitrov, L, Duan, Q, Guo, X, Lange, LA, Nalls, MA, Okut, H, Tajuddin, SM, Tayo, BO, Vedantam, S, Bradfield, JP, Chen, G, Chen, WM, Chesi, A, Irvin, MR, Padhukasahasram, B, Smith, JA, Zheng, W, Allison, MA, Ambrosone, CB, Bandera, EV, Bartz, TM, Berndt, SI, Bernstein, L, Blot, WJ, Bottinger, EP, Carpten, J, Chanock, SJ, Chen, YDI, Conti, DV, Cooper, RS, Fornage, M, Freedman, BI, Garcia, M, Goodman, PJ, Hsu, YHH, Hu, J, Huff, CD, Ingles, SA, John, EM, Kittles, R, Klein, E, Li, J, McKnight, B, Nayak, U, Nemesure, B, Ogunniyi, A, Olshan, A, Press, MF, Rohde, R, Rybicki, BA, Salako, B, Sanderson, M, Shao, Y, Siscovick, DS, Stanford, JL, Stevens, VL, Stram, A, Strom, SS, Vaidya, D, Witte, JS, Yao, J, Zhu, X, Ziegler, RG, Zonderman, AB, Adeyemo, A, Ambs, S, Cushman, M, Faul, JD, Hakonarson, H, Levin, AM, Nathanson, KL, and Ware, EB
- Abstract
© 2017 Public Library of Science. All rights reserved. Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMIfrom the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMIand eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMIin African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMIwhen combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI(SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (
- Published
- 2017
8. Abstract P6-02-08: Modulation of indoleamine 2, 3-dioxygenase (IDO1) expression in breast cancer cells by activated CD8+ T cells is controlled by DNA promoter methylation
- Author
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Gu, F, primary, Noonepalle, SK, additional, Lee, E-J, additional, Choi, J-H, additional, Shull, AY, additional, Pei, L, additional, Sreekumar, A, additional, Ambs, S, additional, and Shi, H, additional
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- 2017
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9. Abstract P5-09-02: Breast cancer risk prediction using a polygenic risk score in women of African ancestry: Findings from GWAS in breast cancer in the African diaspora
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Wang, S, primary, Qian, F, additional, Zheng, Y, additional, Ogundiran, T, additional, Ojengbede, O, additional, Zheng, W, additional, Blot, W, additional, Nathanson, KL, additional, Hennis, A, additional, Nemesure, B, additional, Ambs, S, additional, Olopade, OI, additional, and Huo, D, additional
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- 2017
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10. Abstract P5-08-38: Low lactate dehydrogenase B expression correlates with decreased distant-metastasis free- and recurrence-free survival post-chemotherapy in basal-like breast cancer
- Author
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Dean-Colomb, W, primary, Tan, M, additional, Tang, W, additional, Ambs, S, additional, and Yates, C, additional
- Published
- 2016
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11. Abstract P2-05-15: NOS2&COX2 activation of TLR4 & EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation
- Author
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Glynn, S, primary, Garrrido-Cuesta, P, additional, Wink, D, additional, Ridnour, L, additional, Ambs, S, additional, Keane, M, additional, Walsh, E, additional, and Callagy, G, additional
- Published
- 2016
- Full Text
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12. Absract
- Author
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Kaszkin, Marietta, Kinzel, Volker, Maly, Karl, Bichler, Irina, Lang, Florian, Grunicke, Hans H., Pepperkok, R., Jakobi, R., Lorenz, P., Ansorge, W., Pyerin, W., Borowski, P., Harbers, M., Ludwig, A., Kischel, T., Hilz, H., Eckert, K., Granetzny, A., Fischer, J., Grosse, R., Manch, V., Wehner, S., Kornhuber, B., Ebener, U., Müller-Decker, K., Fürstenberger, G., Vogt, I., Marks, F., Graschew, G., Küsel, A., Hull, W., Lorenz, W., Thielmann, H. W., Degen, Gisela H., Freyberger, Alexius, Müller, A., Linscheid, M., Hindermeier, Ulrike, Jorritsma, Ute, Golka, K., Föllmann, W., Peter, H., Bolt, H. M., Monnerjahn, S., Phillips, D. N., Never, A., Seidel, A., Glatt, A. R., Wiench, K., Frei, E., Schroth, P., Wiessler, M., Schäfer, T., Hergenhahn, M., Hecker, E., Proft, D., Bartholmes, P., Bagewadikar, R. S., Bertram, B., Frank, N., Leibersperger, Hanno, Gschwendt, Michael, Marks, Friedrich, Fasco, S., Plein, Peter, Schiess, Karin, Seidler, Lothar, Jacobi, T., Besemfelder, E., Stephan, M., Lehmann, W. D., Grell, M., Thoma, B., Scheurich, P., Meyer, Markus, Grunicke, Hans, Jaques G., Wegmann B., Ravemann K., Popanda, Odilia, Thielmann, Heinz Walter, Voss, H., Wirkner, U., Werner, Dieter, Strand, D., Kalmes, A., Walther, H. -P., Mechler, B., Schirrmacher, S. Volker, Kinzel, V., Hess, R., Hanagarth, H. -G., Hässler, C., Brandner, G., Ertel, Christian, Gückel, B., Schirrmacher, V., Kyewski, B. A., Bogdahn U., Jachimczak P., Schneider J., Brysch W., Schlingensiepen W., Drenkard D., Behl C., Winkler J., Apfel R., Meixensberger J., Stulle, K., Marquardt, P., Vollmers, H. P., Müller, J., Müller-Hermelink, H. -K., Schuermann, M., Seemann, G., Ptok, Angelika, Ptok, M., Carey, T. E., Steffen M., Nitz U. C., Everding B., Hölzel F., Kantwerk-Funke, G., Boll, G., Zänker, K. S., Everding, B., Steffen, M., Hölzel, P., Heymanns, J., Hennig, C., Rotsch, M., Havemann, K., Fischer, Jürgen R., Stehr, Sabine, Lahm, Harald, Drings, Peter, Krammer, Peter H., Kirsch M., Strubel A., Kist A., Hinn R., Fischer H., Buttler A., Schackert G., Friedenauer, S., Lindner, D., Marczynski, B., Karcls, H., Goergens, H. W., Epe, B., Müller, E., Schütze, D., Boiteux, S., Eder, E., Deininger, C., Hoffman, C., Scherer, E., Vermeulen, E., van Kranen, H. J., Bax, J., Woutersen, R. A., van Kreijl, C. F., Schurich, B., Hagedorn, H., Kamp, E., Eisenbrand, G., Spiegelhalder B., Bolm-Audorff U., Bienfait H. G., Preussmann R., Wacker, C. -D., Preussmann, R., Kehl, H., Spiegelhalder, B., Akkan, Z., Ries, J., Meger, M., Shephard, S. E., Gunz, D., Lutz, W. K., Tricker, A. R., Kurnar, R., Siddiqi, M., Mende, P., Pfundstein, B., Scholl, A., Janzowski, C., Jacob, D., Goelzer, P., Henn, I., Zankl, H., Zimlich, K. -H., Gansewendt, Barbara, Thier, Ricarda, Schroeder, K. R., Hallier, E., Moeckel, G., Heiden, W., Waldherr-Teschner, M., Brickmann, J., Roeser, H., Krauter, G., Scherer, G., Krätschmer, A., Hauenstein, H., Adlkofer, F., Fernando, R. C., Schmeiser, H. H., Nicklas, W., Pfau, Wolfgang, Phillips, David H., Scheckenbach, S., Cantoreggi, S., Leutbecher, Monika, Ottenwälder, H., Föst, U., Baumgart, P. M., Kliem, H. -C., Data, S., Pfeiffer, C., Fuchs, A., Schmezer, P., Kuchenmeister, F., Pool-Zober, B. L., Liegibel, U. M., Pool-Zobel, B. L., Steeb, L., Friesel, H., Schneider, Th., Scherf, H. R., Buchmann, A., Bauer-Hofmann, R., Mahr, J., Schwarz, M., Schmidt, R., Rippmann, F., Steinbauer, B., Zlfu, P., Bunk, B., Hefter, W., Klinga, K., Berger, M. R., Robertson, L. W., Luebeck, G., Moolgavkar, S., Torsten U., Kowalczyk-Wagner M., Weitzel H., Zechel, Ch., Peters, H., Anders, F., Ambs, S., Kirchner, T., Neumann, H. -G., Einig, C., Eigenbrodt, E., Oesterle, D., Deml, E., Weisse, G., Gerbracht, U., Stumpf, H., Filsingcr, E., Bannasch, P., Muster, W., Cikryt, P., Münzel, P., Röhrdanz, E., Bock, K. W., Lipp, H. -P., Wiesmüller, T., Hagenmaier, H., Schrenk, D., Karger, A., Bauer, G., Höfler, P., Götschl, M., Viesel, E., Jürgensmeier, J., Schaefer, D., Picht, G., Kiefer, J., Krieg, P., Schnapke, R., Feil, S., Wagner, E., Schleenbecker, U., Anders, A., Gross, M. M., Unger, S., Stanbridge, E. J., Boukamp, Petra, Pascheberg, Ulrich, Fusenig, Norbert E., Abken, H., Weidle, U. H., Grummt, F., Willecke, K., Schäfer, R., Hajnal, A., Balmer, I., Klemenz, R., Goretzki, P. E., Reishaus, H., Demeure, M., Haubruck, H., Lyons, J., Röher, H. D., Trouliaris, Sylvia, Hadwiger-Fangmeier, Angelika, Simon, Elke, Niemann, Heiner, Tamura, Teruko, Westphal, G., Turner, Elke, Karels, H., Blaszkewicz, M., Stopper, Helga, Schiffmann, Dietmar, De Boni, Umberto, Schuler, M., Schnitzler, R., Metzler, M., Pfeiffer, E., Aulenbacher, R., Langhof, T., Schröder, K. R., Saal, K., Müller-Hermelink, H. K., Henn W., Seitz G., Lagoda P., Christmann A., Blin N., Welter C., Adam, D., Fömzler, D., Winkler, C., Mäueler, W., Schartl, M., Theisinger B., Schüder G., Rüther U., Nunnensiek C., Müller H. A. G., Rupp W., Lüthgens M., Jipp P., Kinzler, I., Gulich, M., Seidel, H. J., Clark, O. H., McCormick, F., Bourne, H. R., Gieseler, F., Boege, F., Biersack, H., Spohn, B., Clark, M., Wilms, K., Boege, Fritz, Gieseler, Frank, Biersack, Harald, Clark, Michael, Wllms, Klaus, Polack, Axel, Strobl, Lothar, Feederle, Regina, Schweizer, Matthias, Eick, Dirk, Bornkamm, Georg W., Kopun M., Scherthan H., Granzow C., Janiaud, P., Rueß, D., Mechler, B. M., Strauss, P. G., Erfle, V., Fritsche, M., Haessler, C., Christiansen, H., Schestag, J., Christiansen, N. M., Lampert, F., Schulz, Wolfgang A., Hasse, Andreas, Sies, Helmut, Orend, G., Kuhlmann, I., Doerfler, W., Behn-Krappa, A., Hölker, I., Sandaradura de Silva, U., Smola, Ute, Hennig, Dagmar, Hadviger-Fangmeier, Angelika, Schütz, Burkhard, Kerler R., Rabes H. M., Dölken, G., Fauser, A. A., Kerkert, R., Ragoczy, U., Fritzen, R., Lange, W., Finke, J., Nowicki, B., Schalipp, E., Siegert, W., Mertelsmann, R., Schilling, U., Sinn, H. J., Maier-Borst, W., Friedrich, E. A., Löhde E., Lück M., Raude H., Schlicker H., Barzen G., Kraas E., Milleck, J., Keymer, R., Störkel, S., Reichert, T., Steinbach, F., Lippold, R., Thoenes, W., Wagner, W., Reiffen, K. -A., Bardosi, A., Brkovic, D., Gabius, H. -J., Brandt B., Jackisch C., Seitzer D., Hillebrand M., Habermann, F. A., Rabes, H. M., Zeindl-Eberhart, Evelyn, Robl, C., Röttgen, V., Nowak, C., Richter-Reichhelm, H. -B., Waldmann, V., Suchy, B., Zietz, Ch., Sarafoff, M., Ostermayr, Richard, Rabes, Hartmut M., Lorenz, J., Friedberg, T., Paulus, W., Ferlinz, R., Oesch, F., Jähde, E., Glüsenkamp, K. -H., Tietze, L. F., Rajewsky, M. F., Chen, G., Hutter, K. -J., Bullerdiek, J., Zeller, W. J., Schirner, M., Schneider, M. R., Zbu, P., Gebelein, M., Naser-Hijazi, B., Hynes, Nancy E., Reinhardt, M., Heyl, P., Schmähl, D., Presek, P., Liebenhoff, U., Findik, D., Hartmann, G. H., Fischer, H., Kliesch, C., Schackert, G., Albert, F., Kunze, S., Wannnenmacher, M., Boese-Landgraf, J., Lorenz, E., Albrecht, D., Dulce, M., Aigner, K. R., Thiem, N., Müller, H., Leonardi, M., Bogdahn, U., Justh, A., Drenkard, D., Lutz, M., Apfel, R., Behl, C., Lang, E., Lieth, C. W. v. d., Sinn, H., Betsch, B. R., Hengstler, Jan Georg, Fuchs, Jürgen, Oesch, Franz, Busch, F. J., Cato, A. B. C., Schied, G., Tang, W., Bogdahn U., Richter B., Schaefer, C., Kelleher, D. K., Vaupel, P., Mundt, D., Bartsch, H. H., Meden, H., Meyer, M., Vehmeyer, K., Mull, R., Kuhn, W., Hoffmann, S., Berger, D., Fiebig, H., Moog, Ch., Luu, B., Frühauf, S., Keppler, B. K., Galeano, A., Valenzuela-Paz, P., Klenner, T., Stadler, H., Golomb, G., Breuer, E., Voegeli, R., Hilgard, P., Nowrousian, H. R., Aulenbacher, P., Winterhalter, B., Granson, C., Stöhr, M., Ponstingl, H., Granzow, C., Drings, P., Osswald, H., Sobottka, S. B., Amtmann, E., Sauer, G., Hornung, B., Volland, S., Kahl, S., Gerspach, R., Matz, B., Schmidt, J., Lipp, M., Brehm, G., Luz, A., Rüther, U., Wendel, S., Strauß, P. G., Erflte, V., Greehmann, S., Zobel, A., Kalkbrenner, F., Vorbrüggen, G., Moelling, K., Iftner, T., Müller, A. H., Fuchs, P. G., Pfister, H., Cichutek, Klaus, Treinies, Iris, Lang, Matthias, Braun, C., Denner J., Norley S., Kurth R., Music, L., Wiestler, O. D., Aguzzi, A., von Deimling, A., Schneemann, M., Elbl, R., Kleihues, P., Land, H., Hohn, H. -P., Höök, M., Denker, H. -W., Kemmner, W., Zaar, K., Jones, Peter A., Kath, R., Herlyn, M., Maier, P., Schawalder, H. P., Elsner, J., Parzefall, W., Erber, E., Sedivy, R., Schulte-Hermann, R., Hemmer, J., Tomakidi, P., Boukamp, P., Breitkreutz, D., Fusenig, N. E., Kallinowski, F., Strauss, W., Brownell, A. L., Bassukas, I. D., Vester, G., Maurer-Schultze, B., Langbein, L., Kosmehl, H., Katenkamp, D., Spiess, Eberhard, Trefz, Günther, Ebert, Werner, Jordan, Peter, Kübler, Dieter, Lichtner, Rosemarie B., Wiedemuth, Marion, Kittmann, Annette, Ullrich, Axel, Khazaie, Khashayarsha, Kowitz, Aiga, Kadmon, Guni, Altevogt, Peter, Frixen, U. H., Behrens, J., Schipper, J., Sachs, M., Birchmeier, H., Hackenberg, R., Hawighorst, Th., Hofmann, J., Beato, H., Schulz, K. -D., Erbil, C., Maasberg, M., Kunz, L. A., Simm, A., Adam, G., Mueller-Klieser, W., Kaufmann, Andreas M., Stoeck, Michael, Hülsen A., Boukamp P., Game S., Donnelly M., Fusenig N. E., Stark, H. -J., Schlingensiepen K. -H., Kurzik-Dumke U., Phannavong B., Gundacker D., Gateff E., Gabius, S., Joshi, S. S., Franz, H., John, N. J., Grümmer, R., Denker, H. W., Gross, M. W., and Karbach, U.
- Published
- 1991
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13. Reprogramming of miRNA networks in cancer and leukemia
- Author
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Volinia, S, Galasso, M, Costinean, S, Tagliavini, L, Gamberoni, G, Drusco, A, Marchesini, J, Mascellani, N, Sana, M. E., Abu Jarour, R, Desponts, C, Teitell, M, Baffa, R, Aqeilan, R, Iorio, M. V., Taccioli, Cristian, Garzon, R, Di Leva, G, Fabbri, M, Catozzi, M, Previati, M, Ambs, S, Palumbo, T, Garofalo, M, Veronese, A, Bottoni, A, Gasparini, P, Harris, C. C., Visone, R, Pekarsky, Y, de la Chapelle, A, Bloomston, M, Dillhoff, M, Rassenti, L. Z., Kipps, T. J., Huebner, K, Pichiorri, F, Lenze, D, Cairo, S, Buendia, M. A., Pineau, P, Dejean, A, Zanesi, N, Rossi, S, Calin, G. A., Liu, C, G, Palatini, J, Negrini, M, Vecchione, A, Rosenberg, A, and Croce, C. M.
- Published
- 2010
14. Relationship Between p53 Mutations and Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer
- Author
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Ambs, S., Bennett, W. P., Merriam, W. G., Ogunfusika, M. O., Oser, S. M., Harrington, A. M., Shields, P. G., Emanuela Felley-Bosco, Hussain, S. P., and Harris, C. C.
- Subjects
Adenoma ,Cancer Research ,Carcinoma ,DNA Mutational Analysis ,Adenoma/enzymology ,Adenoma/genetics ,Carcinoma/enzymology ,Carcinoma/genetics ,Colonic Polyps/enzymology ,Colonic Polyps/genetics ,Colorectal Neoplasms/enzymology ,Colorectal Neoplasms/genetics ,CpG Islands ,DNA, Neoplasm/genetics ,Genes, p53 ,Humans ,Models, Biological ,Mutagenesis ,Neoplasm Proteins/biosynthesis ,Neoplasm Proteins/genetics ,Nitric Oxide/metabolism ,Nitric Oxide Synthase/biosynthesis ,Nitric Oxide Synthase/genetics ,Nitric Oxide Synthase Type II ,Colonic Polyps ,DNA, Neoplasm ,Nitric Oxide ,Neoplasm Proteins ,Oncology ,Nitric Oxide Synthase ,Colorectal Neoplasms - Published
- 1999
15. A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis
- Author
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Subramanian, M, primary, Francis, P, additional, Bilke, S, additional, Li, X L, additional, Hara, T, additional, Lu, X, additional, Jones, M F, additional, Walker, R L, additional, Zhu, Y, additional, Pineda, M, additional, Lee, C, additional, Varanasi, L, additional, Yang, Y, additional, Martinez, L A, additional, Luo, J, additional, Ambs, S, additional, Sharma, S, additional, Wakefield, L M, additional, Meltzer, P S, additional, and Lal, A, additional
- Published
- 2014
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16. Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers
- Author
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Zheng, Y., primary, Ogundiran, T. O., additional, Falusi, A. G., additional, Nathanson, K. L., additional, John, E. M., additional, Hennis, A. J. M., additional, Ambs, S., additional, Domchek, S. M., additional, Rebbeck, T. R., additional, Simon, M. S., additional, Nemesure, B., additional, Wu, S.-Y., additional, Leske, M. C., additional, Odetunde, A., additional, Niu, Q., additional, Zhang, J., additional, Afolabi, C., additional, Gamazon, E. R., additional, Cox, N. J., additional, Olopade, C. O., additional, Olopade, O. I., additional, and Huo, D., additional
- Published
- 2013
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17. MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer
- Author
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Hudson, R S, primary, Yi, M, additional, Esposito, D, additional, Glynn, S A, additional, Starks, A M, additional, Yang, Y, additional, Schetter, A J, additional, Watkins, S K, additional, Hurwitz, A A, additional, Dorsey, T H, additional, Stephens, R M, additional, Croce, C M, additional, and Ambs, S, additional
- Published
- 2012
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18. Expression of Human Endogenous Retrovirus Type K Envelope Protein is a Novel Candidate Prognostic Marker for Human Breast Cancer
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Zhao, J., primary, Rycaj, K., additional, Geng, S., additional, Li, M., additional, Plummer, J. B., additional, Yin, B., additional, Liu, H., additional, Xu, X., additional, Zhang, Y., additional, Yan, Y., additional, Glynn, S. A., additional, Dorsey, T. H., additional, Ambs, S., additional, Johanning, G. L., additional, Gu, L., additional, and Wang-Johanning, F., additional
- Published
- 2011
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19. Interactions among genes, tumor biology and the environment in cancer health disparities: examining the evidence on a national and global scale
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Wallace, T. A., primary, Martin, D. N., additional, and Ambs, S., additional
- Published
- 2011
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20. A functional SNP in the leader sequence of the manganese superoxide dimutase gene is a predictor of breast cancer patient survival and response to chemotherapy.
- Author
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Glynn, SA, primary, Boersma, BJ, additional, Howe, TM, additional, Ridnour, L, additional, Wink, D, additional, Edvardsen, H, additional, Børresen-Dale, A, additional, and Ambs, S, additional
- Published
- 2009
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21. Aberrant inducible nitric oxide synthase expression predicts poor survival in estrogen receptor negative breast cancer, and is associated with a gene expression signature similar to that of basal-like breast cancer.
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Glynn, SA, primary, Boersma, BJ, additional, Howe, TM, additional, Ridnour, L, additional, Wink, D, additional, Yi, M, additional, Yvantis, H, additional, and Ambs, S, additional
- Published
- 2009
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22. B5. iNOS expression is associated with basal-like breast cancer phenotype and predicts poor survival in ERneg breast cancer
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Glynn, S., primary, Boersma, B., additional, Martin, D., additional, Howe, T., additional, Ridnour, L., additional, Wink, D., additional, Yi, M., additional, Stephens, R., additional, Yfantis, H., additional, and Ambs, S., additional
- Published
- 2007
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23. The mannose-binding lectin (MBL2) haplotype and breast cancer: an association study in African-American and Caucasian women
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Bernig, T., primary, Boersma, B. J., additional, Howe, T. M., additional, Welch, R., additional, Yadavalli, S., additional, Staats, B., additional, Mechanic, L. E., additional, Chanock, S. J., additional, and Ambs, S., additional
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- 2006
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24. RESPONSE: Re: Relationship Between p53 Mutations and Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer
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Ambs, S., primary and Harris, C. C., additional
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- 1999
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25. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53
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Ambs, S, primary, Bennett, WP, additional, Merriam, WG, additional, Ogunfusika, MO, additional, Oser, SM, additional, Khan, MA, additional, Jones, RT, additional, and Harris, CC, additional
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- 1998
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26. Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53.
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Forrester, K, primary, Ambs, S, additional, Lupold, S E, additional, Kapust, R B, additional, Spillare, E A, additional, Weinberg, W C, additional, Felley-Bosco, E, additional, Wang, X W, additional, Geller, D A, additional, Tzeng, E, additional, Billiar, T R, additional, and Harris, C C, additional
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- 1996
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27. Role of extracellular calcium and calcium stores in the intracellular calcium rise induced by diethylstilboestrol in C6 rat glioma cells
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Tas, P., primary, Ambs, S., additional, Stopper, H., additional, Koschel, K., additional, and Schiffmann, D., additional
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- 1995
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28. The role of nongenotoxic mechanisms in arylamine carcinogenesis.
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Neumann, H G, primary, Ambs, S, additional, and Bitsch, A, additional
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- 1994
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29. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression
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Ambs S, Wg, Merriam, Wp, Bennett, Emanuela Felley-Bosco, Mo, Ogunfusika, Sm, Oser, Klein S, Pg, Shields, Tr, Billiar, and Cc, Harris
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Adenoma ,Vascular Endothelial Growth Factor A ,Lymphokines ,Neovascularization, Pathologic ,Colon ,Vascular Endothelial Growth Factors ,Blotting, Western ,Carcinoma ,Nitric Oxide Synthase Type II ,DNA, Neoplasm ,Endothelial Growth Factors ,Immunohistochemistry ,Polymerase Chain Reaction ,Neoplasm Proteins ,Colonic Neoplasms ,Disease Progression ,Humans ,Tyrosine ,Endothelium, Vascular ,Nitric Oxide Synthase ,Phosphorylation ,DNA Primers - Abstract
An increased expression of nitric oxide synthase (NOS) has been observed in human colon carcinoma cell lines as well as in human gynecological, breast, and central nervous system tumors. This observation suggests a pathobiological role of tumor-associated NO production. Hence, we investigated NOS expression in human colon cancer in respect to tumor staging, NOS-expressing cell type(s), nitrotyrosine formation, inflammation, and vascular endothelial growth factor expression. Ca2+-dependent NOS activity was found in normal colon and in tumors but was significantly decreased in adenomas (P0.001) and carcinomas (Dukes' stages A-D: P0.002). Ca2+-independent NOS activity, indicating inducible NOS (NOS2), is markedly expressed in approximately 60% of human colon adenomas (P0.001 versus normal tissues) and in 20-25% of colon carcinomas (P0.01 versus normal tissues). Only low levels were found in the surrounding normal tissue. NOS2 activity decreased with increasing tumor stage (Dukes' A-D) and was lowest in colon metastases to liver and lung. NOS2 was detected in tissue mononuclear cells (TMCs), endothelium, and tumor epithelium. There was a statistically significant correlation between NOS2 enzymatic activity and the level of NOS2 protein detected by immunohistochemistry (P0.01). Western blot analysis of tumor extracts with Ca2+-independent NOS activity showed up to three distinct NOS2 protein bands at Mr 125,000-Mr 138,000. The same protein bands were heavily tyrosine-phosphorylated in some tumor tissues. TMCs, but not the tumor epithelium, were immunopositive using a polyclonal anti-nitrotyrosine antibody. However, only a subset of the NOS2-expressing TMCs stained positively for 3-nitrotyrosine, which is a marker for peroxynitrite formation. Furthermore, vascular endothelial growth factor expression was detected in adenomas expressing NOS2. These data are consistent with the hypothesis that excessive NO production by NOS2 may contribute to the pathogenesis of colon cancer progression at the transition of colon adenoma to carcinoma in situ.
30. Re: Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer [3] (multiple letters)
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Gallo, O., Iacopo Sardi, Masini, M., Franchi, A., Ambs, S., and Harris, C. C.
31. COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer
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Goodman Julie E, Wink David A, Dorsey Tiffany M, Boersma Brenda J, Ridnour Lisa A, Prueitt Robyn L, Glynn Sharon A, Yfantis Harris G, Lee Dong H, and Ambs Stefan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Methods Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. Results COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Conclusions Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.
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- 2010
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32. NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations
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Ambs Stefan, Fosså Sophie D, Landmark-Høyvik Hege, Shah Anushi, Porter-Gill Patricia, Kohaar Indu, Howe Tiffany M, Arhancet Juan P, Kaushiva Alpana, Edvardsen Hege, Fu Yi-Ping, Naume Bjørn, Børresen-Dale Anne-Lise, Kristensen Vessela N, and Prokunina-Olsson Ludmila
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)+ versus ER- cancer. Results We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. Conclusion This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.
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- 2010
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33. Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology
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Rivoltini Licia, Ribas Antoni, Pos Zoltan, Petricoin Emanuel F, Palucka A Karolina, Nishikawa Hiroyoshi, Nakamura Kiminori, Mayrand-Chung Shawmarie, Masucci Giuseppe, Matsubara Hisahiro, Malyguine Anatoli, Maio Michele, Lotze Michael T, Liotta Lance, Lehmann Paul V, Kleen Thomas O, Kirkwood John M, Kawakami Yutaka, Kato Kazunori, Kashani-Sabet Mohammed, Kanamoto Akira, Jinushi Masahisa, Jacobson James, Hirohashi Yoshihiko, Imai Kohzoh, Fridman Wolf, Eremin Oleg, Doki Yuichiro, Chaussabel Damien, Akutsu Yasunori, Ambs Stefan, Wigginton Jon M, Lee Peter P, Khleif Samir N, Fox Bernard A, Disis Mary L, Butterfield Lisa H, Wang Ena, Thurin Magdalena, Sato Marimo, Tahara Hideaki, Sato Noriyuki, Shiku Hiroshi, Slingluff Craig L, Streicher Howard, Stroncek David F, Takeuchi Hiroya, Toyota Minoru, Wada Hisashi, Wu Xifeng, Wulfkuhle Julia, Yaguchi Tomonori, Zeskind Benjamin, Zhao Yingdong, Zocca Mai-Britt, and Marincola Francesco M
- Subjects
Medicine - Abstract
Abstract Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that might be added to the list of known entities applicable in immunotherapy trials. The need for a systematic approach to biomarker discovery that takes advantage of powerful high-throughput technologies was recognized; it was clear from the current state of the science that immunotherapy is still in a discovery phase and only a few of the current biomarkers warrant extensive validation. It was, finally, clear that, while current technologies have almost limitless potential, inadequate study design, limited standardization and cross-validation among laboratories and suboptimal comparability of data remain major road blocks. The institution of an interactive consortium for high throughput molecular monitoring of clinical trials with voluntary participation might provide cost-effective solutions.
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- 2009
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34. Association of MTHFR gene polymorphisms with breast cancer survival
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Mechanic Leah E, Goodman Julie E, Howe Tiffany M, Boersma Brenda J, Martin Damali N, Chanock Stephen J, and Ambs Stefan
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. Methods African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival. Results We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.05–4.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.31–1.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.17–6.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.12–1.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, pinteraction = 0.088; C677T, pinteraction = 0.026). Conclusion We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival.
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- 2006
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35. Mutagenesis of nitric oxide (NO) versus ethylnitrosurea (ENU): Phenotypic and genotypic approaches in human cells
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Felley-Bosco, E., Mirkovitch, J., Ambs, S., Macé, K., Pfeifer, A., Keefer, L.K., and Harris, C.C.
- Published
- 1994
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36. A microRNA expression signature of human solid tumors defines cancer gene targets
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Andrea Vecchione, Chang Gong Liu, Stefan Ambs, Robyn L. Prueitt, Rosa Visone, Giovanni Lanza, Manuela Ferracin, Curtis C. Harris, Massimo Negrini, Amelia Cimmino, George A. Calin, Marilena V. Iorio, Stefano Volinia, Carlo M. Croce, Fabio Petrocca, Nozumu Yanaihara, Claudia Roldo, Aldo Scarpa, Volinia S., Calin G. A., Liu C. G., Ambs S., Cimmino A., Petrocca F., Visone R., Iorio M., Roldo C., Ferracin M., Prueitt R. L., Yanaihara N., Lanza G., Scarpa A., Vecchione A., Negrini M., Harris C. C., and Croce C. M.
- Subjects
Microarray ,Biology ,medicine.disease_cause ,Transcriptome ,Neoplasms ,microRNA ,Tumor Cells, Cultured ,medicine ,BREAST-CANCER ,Humans ,Genes, Tumor Suppressor ,microarray ,transcriptome ,tumorigenesis ,Oligonucleotide Array Sequence Analysis ,Multidisciplinary ,CHRONIC LYMPHOCYTIC-LEUKEMIA ,Retinoblastoma ,Gene Expression Profiling ,Cancer ,Biological Sciences ,Oncomir ,medicine.disease ,Molecular biology ,Gene expression profiling ,MicroRNAs ,B-CELL LYMPHOMAS ,RNA ,Carcinogenesis ,Genes, Neoplasm - Abstract
Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers. From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion of overexpressed miRNAs. Among these miRNAs are some with well characterized cancer association, such as miR-17-5p , miR-20a , miR-21 , miR-92 , miR-106a , and miR-155 . The predicted targets for the differentially expressed miRNAs are significantly enriched for protein-coding tumor suppressors and oncogenes ( P < 0.0001). A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes were confirmed experimentally. Our results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes.
- Published
- 2006
37. MIF/NR3C2 axis regulates glucose metabolism reprogramming in pancreatic cancer through MAPK-ERK and AP-1 pathways.
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Yang S, Tang W, Azizian A, Gaedcke J, Ohara Y, Cawley H, Hanna N, Ghadimi M, Lal T, Sen S, Creighton CJ, Gao J, Putluri N, Ambs S, and Hussain P
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- Humans, Animals, Mice, Cell Line, Tumor, MAP Kinase Signaling System, Gene Expression Regulation, Neoplastic, Hexokinase metabolism, Hexokinase genetics, Cell Proliferation, Signal Transduction, Metabolic Reprogramming, Macrophage Migration-Inhibitory Factors metabolism, Macrophage Migration-Inhibitory Factors genetics, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Pancreatic Neoplasms genetics, Glucose metabolism, Intramolecular Oxidoreductases metabolism, Intramolecular Oxidoreductases genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Transcription Factor AP-1 metabolism
- Abstract
Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2 and LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2 and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of the mitogen-activated protein kinase-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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38. ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.
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Ohara Y, Liu H, Craig AJ, Yang S, Moreno P, Dorsey TH, Cawley H, Azizian A, Gaedcke J, Ghadimi M, Hanna N, Ambs S, and Hussain SP
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- Humans, Cell Line, Tumor, Male, Female, Metabolome, Autophagy-Related Proteins metabolism, Autophagy-Related Proteins genetics, Neoplasm Invasiveness, Transcriptome, Middle Aged, Metabolic Reprogramming, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Cell Movement, Gene Expression Regulation, Neoplastic
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2024
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39. Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.
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Sun X, Verma SP, Jia G, Wang X, Ping J, Guo X, Shu XO, Chen J, Derkach A, Cai Q, Liang X, Long J, Offit K, Oh JH, Reiner AS, Watt GP, Woods M, Yang Y, Ambrosone CB, Ambs S, Chen Y, Concannon P, Garcia-Closas M, Gu J, Haiman CA, Hu JJ, Huo D, John EM, Knight JA, Li CI, Lynch CF, Mellemkjær L, Nathanson KL, Nemesure B, Olopade OI, Olshan AF, Pal T, Palmer JR, Press MF, Sanderson M, Sandler DP, Troester MA, Zheng W, Bernstein JL, Buas MF, and Shu X
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- Humans, Female, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Case-Control Studies, Risk Factors, Genome-Wide Association Study, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment., (©2024 American Association for Cancer Research.)
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- 2024
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40. LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism.
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Ohara Y, Craig AJ, Liu H, Yang S, Moreno P, Dorsey TH, Cawley H, Azizian A, Gaedcke J, Ghadimi M, Hanna N, Ambs S, and Hussain SP
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- Humans, Male, Female, Cell Movement, Cell Line, Tumor, Prognosis, Middle Aged, LIM Domain Proteins metabolism, LIM Domain Proteins genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms mortality, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal mortality, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Cell Proliferation, Gene Expression Regulation, Neoplastic
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC., (Published by Oxford University Press 2024.)
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- 2024
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41. Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors.
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Ridnour LA, Cheng RY, Kedei N, Somasundaram V, Bhattacharyya DD, Basudhar D, Wink AL, Walke AJ, Kim C, Heinz WF, Edmondson EF, Butcher DO, Warner AC, Dorsey TH, Pore M, Kinders RJ, Lipkowitz S, Bryant RJ, Rittscher J, Wong ST, Hewitt SM, Chang JC, Shalaby A, Callagy GM, Glynn SA, Ambs S, Anderson SK, McVicar DW, Lockett SJ, and Wink DA
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- Animals, Mice, Female, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms immunology, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms radiotherapy, Indomethacin pharmacology, Indomethacin therapeutic use, Cell Line, Tumor, Humans, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms drug therapy, Cyclooxygenase Inhibitors pharmacology, Cyclooxygenase Inhibitors therapeutic use, Nucleotidyltransferases metabolism, Interferon Type I metabolism, Cyclooxygenase 2 metabolism, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating drug effects, Mice, Inbred BALB C, Membrane Proteins metabolism, Signal Transduction drug effects, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic drug effects
- Abstract
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
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- 2024
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42. Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.
- Author
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Ping J, Jia G, Cai Q, Guo X, Tao R, Ambrosone C, Huo D, Ambs S, Barnard ME, Chen Y, Garcia-Closas M, Gu J, Hu JJ, John EM, Li CI, Nathanson K, Nemesure B, Olopade OI, Pal T, Press MF, Sanderson M, Sandler DP, Yoshimatsu T, Adejumo PO, Ahearn T, Brewster AM, Hennis AJM, Makumbi T, Ndom P, O'Brien KM, Olshan AF, Oluwasanu MM, Reid S, Yao S, Butler EN, Huang M, Ntekim A, Li B, Troester MA, Palmer JR, Haiman CA, Long J, and Zheng W
- Subjects
- Adult, Aged, Female, Humans, Middle Aged, Black People genetics, Case-Control Studies, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Receptors, Estrogen genetics, Receptors, Estrogen metabolism, Black or African American, United States, Breast Neoplasms genetics, Genetic Predisposition to Disease, Transcriptome
- Abstract
African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations., (© 2024. The Author(s).)
- Published
- 2024
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43. Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.
- Author
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Jia G, Ping J, Guo X, Yang Y, Tao R, Li B, Ambs S, Barnard ME, Chen Y, Garcia-Closas M, Gu J, Hu JJ, Huo D, John EM, Li CI, Li JL, Nathanson KL, Nemesure B, Olopade OI, Pal T, Press MF, Sanderson M, Sandler DP, Shu XO, Troester MA, Yao S, Adejumo PO, Ahearn T, Brewster AM, Hennis AJM, Makumbi T, Ndom P, O'Brien KM, Olshan AF, Oluwasanu MM, Reid S, Butler EN, Huang M, Ntekim A, Qian H, Zhang H, Ambrosone CB, Cai Q, Long J, Palmer JR, Haiman CA, and Zheng W
- Subjects
- Humans, Female, Case-Control Studies, Risk Factors, Triple Negative Breast Neoplasms genetics, Alleles, Multifactorial Inheritance genetics, Middle Aged, Genetic Loci, White People genetics, Genome-Wide Association Study methods, Genetic Predisposition to Disease, Breast Neoplasms genetics, Polymorphism, Single Nucleotide, Black People genetics
- Abstract
We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10
-8 ), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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44. Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.
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Ochs-Balcom HM, Preus L, Du Z, Elston RC, Teerlink CC, Jia G, Guo X, Cai Q, Long J, Ping J, Li B, Stram DO, Shu XO, Sanderson M, Gao G, Ahearn T, Lunetta KL, Zirpoli G, Troester MA, Ruiz-Narváez EA, Haddad SA, Figueroa J, John EM, Bernstein L, Hu JJ, Ziegler RG, Nyante S, Bandera EV, Ingles SA, Mancuso N, Press MF, Deming SL, Rodriguez-Gil JL, Yao S, Ogundiran TO, Ojengbede O, Bolla MK, Dennis J, Dunning AM, Easton DF, Michailidou K, Pharoah PDP, Sandler DP, Taylor JA, Wang Q, O'Brien KM, Weinberg CR, Kitahara CM, Blot W, Nathanson KL, Hennis A, Nemesure B, Ambs S, Sucheston-Campbell LE, Bensen JT, Chanock SJ, Olshan AF, Ambrosone CB, Olopade OI, The Ghana Breast Health Study Team, Conti DV, Palmer J, García-Closas M, Huo D, Zheng W, and Haiman C
- Subjects
- Female, Humans, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Black People genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease
- Abstract
Background: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs., Methods: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG)., Results: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16)., Conclusion: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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45. Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.
- Author
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White JA, Kaninjing ET, Adeniji KA, Jibrin P, Obafunwa JO, Ogo CN, Mohammed F, Popoola A, Fatiregun OA, Oluwole OP, Thorpe RJ Jr, Karanam B, Elhussin I, Ambs S, Tang W, Davis M, Polak P, Campbell MJ, Brignole KR, Rotimi SO, Dean-Colomb W, Odedina FT, and Yates C
- Subjects
- Humans, Male, Exome Sequencing, Quality of Life, Prostate pathology, Axonemal Dyneins genetics, Transcriptional Elongation Factors genetics, Kinesins genetics, Prostatic Hyperplasia genetics, Prostatic Hyperplasia pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Background: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking., Methods: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH., Results: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair., Conclusions: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
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46. S. Perwez Hussain, 1960-2023.
- Author
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Ambs S
- Published
- 2024
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47. Association of neighborhood gentrification with prostate cancer and immune markers in African American and European American men.
- Author
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Pichardo CM, Ezeani A, Pichardo MS, Agurs-Collins T, Powell-Wiley TM, Ryan B, Minas TZ, Bailey-Whyte M, Tang W, Dorsey TH, Wooten W, Loffredo CA, and Ambs S
- Subjects
- Humans, Male, Case-Control Studies, Middle Aged, Aged, Neighborhood Characteristics, United States epidemiology, Biomarkers, Tumor blood, Risk Factors, Residence Characteristics, Residential Segregation, Prostatic Neoplasms immunology, Prostatic Neoplasms blood, Prostatic Neoplasms epidemiology, Prostatic Neoplasms mortality, Prostatic Neoplasms pathology, Black or African American statistics & numerical data, White People statistics & numerical data
- Abstract
Background: Prior studies showed that neighborhood deprivation increases the risk of lethal prostate cancer. However, the role of neighborhood gentrification in prostate cancer development and outcome remains poorly understood. We examined the relationships of gentrification with prostate cancer and serum proteome-defined inflammation and immune function in a diverse cohort., Methods: The case-control study included 769 cases [405 African American (AA), 364 European American (EA) men] and 1023 controls (479 AA and 544 EA), with 219 all-cause and 59 prostate cancer-specific deaths among cases. Geocodes were linked to a neighborhood gentrification index (NGI) derived from US Census data. Cox and logistic regression, and MANOVA, were used to determine associations between NGI, as continuous or quintiles (Q), and outcomes., Results: Adjusting for individual socioeconomic status (SES), continuous NGI was positively associated with prostate cancer among all men (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.01-1.14). AA and low-income men experienced the highest odds of prostate cancer when residing in tracts with moderate gentrification, whereas EA men experienced reduced odds of regional/metastatic cancer with increased gentrification in SES-adjusted analyses. Continuous NGI also associated with mortality among men presenting with localized disease and low-income men in SES-adjusted Cox regression analyses. NGI was not associated with serum proteome-defined chemotaxis, inflammation, and tumor immunity suppression., Conclusions: Findings show that neighborhood gentrification associates with prostate cancer and mortality in this diverse population albeit associations were heterogenous within subgroups. The observations suggest that changing neighborhood socioeconomic environments may affect prostate cancer risk and outcome, likely through multifactorial mechanisms., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2024
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48. SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer.
- Author
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Ohara Y, Tang W, Liu H, Yang S, Dorsey TH, Cawley H, Moreno P, Chari R, Guest MR, Azizian A, Gaedcke J, Ghadimi M, Hanna N, Ambs S, and Hussain SP
- Subjects
- Animals, Humans, Mice, Disease Progression, Gene Expression Regulation, Neoplastic, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Squamous Cell genetics, Pancreatic Neoplasms pathology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits distinct molecular subtypes: classical/progenitor and basal-like/squamous. Our study aimed to identify genes contributing to the development of the basal-like/squamous subtype, known for its aggressiveness. Transcriptome analyses revealed consistent upregulation of SERPINB3 in basal-like/squamous PDAC, correlating with reduced patient survival. SERPINB3 transgene expression in PDAC cells enhanced in vitro invasion and promoted lung metastasis in a mouse PDAC xenograft model. Metabolome analyses unveiled a metabolic signature linked to both SERPINB3 and the basal-like/squamous subtype, characterized by heightened carnitine/acylcarnitine and amino acid metabolism, associated with poor prognosis in patients with PDAC and elevated cellular invasiveness. Further analysis uncovered that SERPINB3 inhibited the cysteine protease calpain, a key enzyme in the MYC degradation pathway, and drove basal-like/squamous subtype and associated metabolic reprogramming through MYC activation. Our findings indicate that the SERPINB3-MYC axis induces the basal-like/squamous subtype, proposing SERPINB3 as a potential diagnostic and therapeutic target for this variant., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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49. Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients.
- Author
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Ridnour LA, Cheng RYS, Heinz WF, Pore M, Gonzalez AL, Femino EL, Moffat R, Wink AL, Imtiaz F, Coutinho L, Butcher D, Edmondson EF, Rangel MC, Wong STC, Lipkowitz S, Glynn S, Vitek MP, McVicar DW, Li X, Anderson SK, Paolocci N, Hewitt SM, Ambs S, Billiar TR, Chang JC, Lockett SJ, and Wink DA
- Abstract
Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER-breast cancers.
- Published
- 2023
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50. NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER- Breast Cancer.
- Author
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Ridnour LA, Heinz WF, Cheng RY, Wink AL, Kedei N, Pore M, Imtiaz F, Femino EL, Gonzalez AL, Coutinho L, Butcher D, Edmondson EF, Rangel MC, Kinders RJ, Lipkowitz S, Wong ST, Anderson SK, McVicar DW, Li X, Glynn SA, Billiar TR, Chang JC, Hewitt SM, Ambs S, Lockett SJ, and Wink DA
- Abstract
Estrogen receptor-negative (ER-) breast cancer is an aggressive breast cancer subtype with limited therapeutic options. Upregulated expression of both inducible nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) in breast tumors predicts poor clinical outcomes. Signaling molecules released by these enzymes activate oncogenic pathways, driving cancer stemness, metastasis, and immune suppression. The influence of tumor NOS2/COX2 expression on the landscape of immune markers using multiplex fluorescence imaging of 21 ER- breast tumors were stratified for survival. A powerful relationship between tumor NOS2/COX2 expression and distinct CD8+ T cell phenotypes was observed at 5 years post-diagnosis. These results were confirmed in a validation cohort using gene expression data showing that ratios of NOS2 to CD8 and COX2 to CD8 are strongly associated with poor outcomes in high NOS2/COX2-expressing tumors. Importantly, multiplex imaging identified distinct CD8+ T cell phenotypes relative to tumor NOS2/COX2 expression in Deceased vs Alive patient tumors at 5-year survival. CD8+NOS2-COX2- phenotypes defined fully inflamed tumors with significantly elevated CD8+ T cell infiltration in Alive tumors expressing low NOS2/COX2. In contrast, two distinct phenotypes including inflamed CD8+NOS2+COX2+ regions with stroma-restricted CD8+ T cells and CD8-NOS2-COX2+ immune desert regions with abated CD8+ T cell penetration, were significantly elevated in Deceased tumors with high NOS2/COX2 expression. These results were supported by applying an unsupervised nonlinear dimensionality-reduction technique, UMAP, correlating specific spatial CD8/NOS2/COX2 expression patterns with patient survival. Moreover, spatial analysis of the CD44v6 and EpCAM cancer stem cell (CSC) markers within the CD8/NOS2/COX2 expression landscape revealed positive correlations between EpCAM and inflamed stroma-restricted CD8+NOS2+COX2+ phenotypes at the tumor/stroma interface in deceased patients. Also, positive correlations between CD44v6 and COX2 were identified in immune desert regions in deceased patients. Furthermore, migrating tumor cells were shown to occur only in the CD8-NOS2+COX2+ regions, identifying a metastatic hot spot. Taken together, this study shows the strength of spatial localization analyses of the CD8/NOS2/COX2 landscape, how it shapes the tumor immune microenvironment and the selection of aggressive tumor phenotypes in distinct regions that lead to poor clinical outcomes. This technique could be beneficial for describing tumor niches with increased aggressiveness that may respond to clinically available NOS2/COX2 inhibitors or immune-modulatory agents.
- Published
- 2023
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