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Your search keyword '"HORMONE-RELATED PROTEIN"' showing total 10 results
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10 results on '"HORMONE-RELATED PROTEIN"'

1. Hypoxia Activates the PTHrP –MEF2C Pathway to Attenuate Hypertrophy in Mesenchymal Stem Cell Derived Cartilage

Author

Stephen J. Elliman, David C. Browe, Frank Barry, Cynthia M. Coleman, Science Foundation Ireland, and Seventh Framework Programme

Subjects
Cartilage, Articular, 0301 basic medicine, PROMOTES, lcsh:Medicine, HORMONE-RELATED PROTEIN, Mice, 0302 clinical medicine, MEF2C, Anaerobiosis, lcsh:Science, IN-VITRO CHONDROGENESIS, Multidisciplinary, MEF2 Transcription Factors, Chemistry, Hyaline cartilage, Cell Hypoxia, Cell biology, DIFFERENTIATION, medicine.anatomical_structure, ATDC5, 030220 oncology & carcinogenesis, Chondrogenesis, EXPRESSION, medicine.medical_specialty, Glycine, LINE, Mesenchymal Stem Cell Transplantation, Article, 03 medical and health sciences, Chondrocytes, In vivo, Cell Line, Tumor, Internal medicine, medicine, Animals, Humans, TRANSPLANTATION, Cartilage, lcsh:R, Mesenchymal stem cell, Parathyroid Hormone-Related Protein, Mesenchymal Stem Cells, Prolyl-Hydroxylase Inhibitors, Hypertrophy, Isoquinolines, CALCIFICATION, Transplantation, 030104 developmental biology, Endocrinology, Cell culture, lcsh:Q
Abstract

Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage. Methods that improve the chondrogenic potential of transplanted MSCs in vivo may be advantageous. In addition, the proclivity of MSC-derived cartilage to undergo hypertrophic differentiation or form bone in vivo also remains a clinical concern. If MSC-derived cartilage was to undergo hypertrophic differentiation in vivo, this would be deleterious in a clinical setting. This study focuses on establishing a mechanism of action by which hypoxia or low oxygen tension can be used to both enhance chondrogenesis and attenuate hypertrophic differentiation of both MSC and ATDC5 derived chondrocytes. Having elucidated a novel mechanism of action, the subsequent goals of this study were to develop an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment.

Published
2019

2. Hypoparathyroidism in pregnancy:review and evidence-based recommendations for management

Author

Khan, Aliya A, Clarke, Bart, Rejnmark, Lars, and Brandi, Maria Luisa

Subjects
MATERNAL HYPOPARATHYROIDISM, Calcium/blood, INTACT PARATHYROID-HORMONE, BONE METABOLISM, Hypoparathyroidism/blood, HORMONE-RELATED PROTEIN, CALCITROPIC HORMONES, Pregnancy Complications/blood, CIRCULATING LEVELS, Pregnancy, Vitamin D Deficiency/blood, CONGENITAL HYPERPARATHYROIDISM SECONDARY, CALCIOTROPIC HORMONES, INTRAUTERINE HYPERPARATHYROIDISM, Hypocalcemia/blood, Humans, Female, CALCIUM-REGULATING HORMONES, Calcitriol/blood
Abstract

Purpose Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy. Methods We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review. Conclusions During pregnancy, calcitriol levels increase by two- to-three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies.

Published
2019

3. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author

Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed

Published
2016

4. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Author

Michailidou, K., Hall, P., Gonzalez-Neira, A., Ghoussaini, M., Dennis, J., Milne, R.L., Schmidt, M.K., Chang-Claude, J., Bojesen, S.E., Bolla, M.K., Wang, Q., Dicks, E., Lee, A., Turnbull, C., Rahman, N., Fletcher, O., Peto, J., Gibson, L., Silva, I.D., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Czene, K., Irwanto, A., Liu, J.J., Waisfisz, Q., Meijers-Heijboer, H., Adank, M., Luijt, R.B. van der, Hein, R., Dahmen, N., Beckman, L., Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Hopper, J.L., Southey, M.C., Makalic, E., Schmidt, D.F., Uitterlinden, A.G., Hofman, A., Hunter, D.J., Chanock, S.J., Vincent, D., Bacot, F., Tessier, D.C., Canisius, S., Wessels, L.F.A., Haiman, C.A., Shah, M., Luben, R., Brown, J., Luccarini, C., Schoof, N., Humphreys, K., Li, J.M., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Couch, F.J., Wang, X.S., Vachon, C., Stevens, K.N., Lambrechts, D., Moisse, M., Paridaens, R., Christiaens, M.R., Rudolph, A., Nickels, S., Flesch-Janys, D., Johnson, N., Aitken, Z., Aaltonen, K., Heikkinen, T., Broeks, A., Van't Veer, L.J., Schoot, C.E. van der, Guenel, P., Truong, T., Laurent-Puig, P., Menegaux, F., Marme, F., Schneeweiss, A., Sohn, C., Burwinke, B., Zamora, M.P., Perez, J.I.A., Pita, G., Alonso, M.R., Cox, A., Brock, I.W., Cross, S.S., Reed, M.W.R., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Henderson, B.E., Schumacher, F., Marchand, L. le, Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Lindblom, A., Margolin, S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Bui, Q.M., Stone, J., Dite, G.S., Apicella, C., Tsimiklis, H., Giles, G.G., Severi, G., Baglietto, L., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Brenner, H., Muller, H., Arndt, V., Stegmaier, C., Swerdlown, A., Ashworth, A., Orr, N., Jones, M., Figueroa, J., Lissowska, J., Brinton, L., Goldberg, M.S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Bruning, T., Radice, P., Peterlongo, P., Manouldan, S., Bonanni, B., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Kristensen, V.N., Anton-Culver, H., Slager, S., Toland, A.E., Edge, S., Fostira, F., Kang, D., Yoo, K.Y., Noh, D.Y., Matsuo, K., Ito, H., Iwata, H., Sueta, A., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Teo, S.H., Yip, C.H., Phuah, S.Y., Cornes, B.K., Hartman, M., Miao, H., Lim, W.Y., Sng, J.H., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Blot, W.J., Signorello, L.B., Cai, Q.Y., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Simard, J., Garcia-Closas, M., Pharoah, P.D.P., Chenevix-Trench, G., Dunning, A.M., Benitez, J., Easton, D.F., Breast Ovarian Canc Susceptibility, Hereditary Breast Ovarian Canc Res, kConFab Investigators, Australian Ovarian Can Study Grp, GENICA Gene Environm Interaction B, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Landsteiner Laboratory, Clinical Haematology, Clinical Genetics, Internal Medicine, Epidemiology, Medical Oncology, Cardiothoracic Surgery, Human genetics, CCA - Oncogenesis, and ~

Subjects
signaling pathway, Genotyping, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, consortium, Biology, Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genetic Loci, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors, Genetic Predisposition to Disease, Genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, common variants, expression, medicine, Polymorphism, gene, hormone-related protein, 030304 developmental biology, Genetic association, 0303 health sciences, Breast cancer susceptibility, Cancer, Single Nucleotide, medicine.disease, confer susceptibility, susceptibility loci, 3. Good health, 14q24.1 rad51l1, TOX3, 030220 oncology & carcinogenesis, genome-wide association
Abstract

Journal article Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10!¿8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. European Community Seventh Framework Programme - grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) peer-reviewed

Published
2013

5. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author

Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Andrew, Lee, Daniel, Barrowdale, Sue, Healey, Sinilnikova, Olga M., Caligo, Maria A., Niklas, Loman, Katja, Harbst, Annika, Lindblom, Brita, Arver, Richard, Rosenquist, Per, Karlsson, Kate, Nathanson, Susan, Domchek, Tim, Rebbeck, Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Zlowocka Perlowska, E., Elzbieta Złowowcka Perłowska, Ana, Osorio, Mercedes, Duran, Raquel, Andres, Javier, Benitez, Ute, Hamann, Hogervorst, Frans B., Van, A., Van Os, Theo A., Senno, Verhoef, Meijers Heijboer, Hanne E. J., Juul, Wijnen, Gomez Garcia, Encarna B., Ligtenberg, Marjolijn J., Mieke, Kriege, Margriet Collee, J., Margreet Gem Ausems, Oosterwijk, Jan C., Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Rogers, Mark T., Alan, Donaldson, Huw, Dorkins, Godwin, Andrew K., Betsy, Bove, Dominique Stoppa Lyonnet, Claude, Houdayer, Bruno, Buecher, De Pauw, A., Antoine Pauw, D. E., Sylvie, Mazoyer, Alain, Calender, Melanie, Leone, Brigitte Bressac De Paillerets, Olivier, Caron, Hagay, Sobol, Marc, Frenay, Fabienne, Prieur, Sandra, Ferrer, Isabelle, Mortemousque, Saundra, Buys, Mary, Daly, Alexander, Miron, Terry, Mb, Terry, Mu, Mary, Terry, Hopper, John L., John, Em, Esther, John M., Melissa, Southey, David, Goldgar, Singer, Christian F., Anneliese Fink Retter, Muy Kheng Tea, Geschwantler Kaulich, D., Daphne, Kaulich, Hansen, Thomas V. O., Nielsen, Finn C., Barkardottir, Rosa B., Mia, Gaudet, Tomas, Kirchhoff, Joseph, V., Joseph, Vijai, Ana Dutra Clarke, Kenneth, Offit, Marion, Piedmonte, Judy, Kirk, David, Cohn, Jean, Hurteau, John, Byron, James, Fiorica, Toland, Amanda E., Marco, Montagna, Cristina, Oliani, Evgeny, Imyanitov, Claudine, Isaacs, Laima, Tihomirova, Ignacio, Blanco, Conxi, Lazaro, Alex, Teule, Del Valle, J., Gayther, Simon A., Kunle, Odunsi, Jenny, Gross, Karlan, Beth Y., Edith, Olah, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Jansen Van Rensburg, E., Elizabeth Van Rensburg, Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorothea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Muranen, Taru A., Bernard, Lesperance, Spurdle, Amanda B., Neuhausen, Susan L., Ding, Yuan C., Xianshu, Wang, Zachary, Fredericksen, Pankratz, Vernon S., Lindor, Noralane M., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Loud, Jennifer T., Andrulis, Irene L., Hilmi, Ozcelik, Anna, Mulligan, Gord, Glendon, Mads, Thomassen, Anne Marie Gerdes, Jensen, Uffe B., Anne Bine Skytte, Kruse, Torben A., Georgia Chenevix Trench, Couch, Fergus J., Jacques, Simard, Easton, Douglas F., Swedish Breast, Cancer Study S. B., Facility, Research H., Study, E., Collaborators, Study G., Investigators, K., Swe Brca Cimba, Embrace, Hebon, Study Gemo Collaborators, Kconfab, Investigators, BMC, Ed., Collaborative Oncological Gene-environment Study - COGS - - EC:FP7:HEALTH2009-05-01 - 2014-01-31 - 223175 - VALID, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Genetics and Population Health Division, Queensland Institute of Medical Research, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Oncology, Lund University Hospital, Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Sahlgrenska University Hospital [Gothenburg], Abramson Cancer Center, University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Postgraduate School of Molecular Medicine, Warsaw Medical University, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Institute of Biology and Molecular Genetics, Universidad de Valladolid [Valladolid] (UVa), Medical Oncology Division, Hospital Clínico de Zaragoza, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Family Cancer Clinic, Netherlands Cancer Institute, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), VU Medical Center, Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, Department of Human Genetics, Radboud University [Nijmegen], Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Department of Genetics, VU University Medical Center [Amsterdam], Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Oncogenetics Team, The Institute of Cancer Research-Royal Marsden NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Addenbrookes Hospital, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Royal Devon & Exeter Hospital, Medical Genetics Unit, University College of London [London] (UCL), Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Department of Medical Genetics, Queen's University [Belfast] (QUB), Oxford Regional Genetics Service, Churchill Hospital Oxford Centre for Haematology, All Wales Medical Genetics Services, Singleton Hospital, Clinical Genetics Department, St Michael's Hospital, North West Thames Regional Genetics Service, Kennedy-Galton Centre, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Clinical Molecular Genetics Laboratory, Fox Chase Cancer Center, Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, Institut Gustave Roussy (IGR), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Consultation de génétique, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Laboratoire de Génétique Chromosomique, CH Chambéry, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Internal Medicine, Huntsman Cancer Institute, Division of Population Science, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Department of Epidemiology, Columbia University [New York], Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Cancer Prevention Institute of California, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Dept of OB/GYN and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Pathology, University of Iceland [Reykjavik]-Landspitali - University Hospital, Epidemiology Research Program, American Cancer Society, Department of Environmental Medicine, New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Australia New Zealand (ANZGOG), Westmead Hospital [Sydney], Ohio State University [Columbus] (OSU), Evanston CCOP - NorthShore University Health System, University of Chicago, Southern Pines Women's Health Center, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Sarasota Memorial Healthcare, Tufts Medical Center, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, U.O.C. di Oncologia, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Latvian Biomedical Research and Study Centre [Rīga], Genetic Counselling Unit, IDIBELL-Catalan Institute of Oncology, Molecular Diagnostic Unit, Department of Preventive Medicine, University of Southern California (USC)-Keck School of Medicine [Los Angeles], University of Southern California (USC), Department of Gynecologic Oncology, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Department of Molecular Genetics, National Institute of Oncology, Cancer Research Initiatives Foundation, Sime Darby Medical Centre-Malaysia and University Malaya Cancer Research Institute-University Malaya Medical Centre, Jonsson Comprehensive Cancer Center at UCLA, Jonsson Comprehensive Cancer Center, UCSF Cancer Risk Program, University of California (UC), Departments of Medicine, Epidemiology, and Biostatistics, UCSF, Cancer Genetics Laboratory, University of Pretoria [South Africa], Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ludwig-Maximilians-Universität München (LMU), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universitätsklinikum Ulm - University Hospital of Ulm, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Heidelberg University Hospital [Heidelberg], University Hospital Carl Gustav Carus, Universität Regensburg (UR), University Hospital Frankfurt a.M., Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Hemato-oncology service, Hôpital du Sacré-Coeur de Montréal, Department of Population Sciences, Beckman Research Institute of City of Hope, Department of Laboratory Medicine and Pathology, Mayo Clinic, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), Cancer Bioimmunotherapy Unit, IRCCS-Centro di Riferimento Oncologico, Università degli Studi di Firenze = University of Florence (UniFI), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Laboratory Medicine, St Michael's Hospital-Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Ontario Cancer Genetics Network, Cancer Care Ontario, Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Skejby Hospital, Department of Laboratory Medicine and Pathology and Health Sciences Research, This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175), from the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program and by the Canadian Breast Cancer Research Alliance-grant #019511. This research was also supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. ACA is a CR-UK Senior Cancer Research Fellow, DFE is CR-UK Principal Research Fellow, GCT is a NHMRC Senior Principal Research Fellow, J.S. is Chairholder of the Canada Research Chair in Oncogenetics, on behalf of CIMBA, SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators and kConFab Investigators, European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), Pediatric Surgery, Neurology, Medical Oncology, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Roswell Park Cancer Institute [Buffalo] (RPCI), Universität Leipzig, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Pomeranian Medical University-International Hereditary Cancer Centre, Radboud university [Nijmegen], University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Georgetown University, University of California, Westfälische Wilhelms-Universität Münster (WWU), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human genetics, and CCA - Oncogenesis

Subjects
Oncology, Medicin och hälsovetenskap, Estrogen receptor, Genome-wide association study, HORMONE-RELATED PROTEIN, Chromosomes, Human, Pair 9 - genetics, Medical and Health Sciences, 0302 clinical medicine, 610 Medical sciences Medicine, CDKN2A, Risk Factors, Genotype, INVESTIGATORS, Chromosomes, Human, Pair 12 - genetics, skin and connective tissue diseases, MAMMOGRAPHIC DENSITY, Medicine(all), 0303 health sciences, BRCA1 Protein, Middle Aged, BRCA2 Protein, 3. Good health, DNA-Binding Proteins, Hereditary Breast and Ovarian Cancer Syndrome - genetics, 030220 oncology & carcinogenesis, Hereditary Breast and Ovarian Cancer Syndrome, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 9, Research Article, Adult, Breast cancer, BRCA1, BRCA2, medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, ddc:610, GENOME-WIDE ASSOCIATION, ddc:611, Genetic Association Studies, 030304 developmental biology, Aged, Gynecology, Chromosomes, Human, Pair 12, CONSORTIUM, BRCA1 Protein - genetics, ALLELES, medicine.disease, BRCA2 Protein - genetics, Cancer and Oncology, GENETIC MODIFIERS, Ovarian cancer, Transcription Factors
Abstract

INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers., published_or_final_version

Published
2012

6. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

Author

Sanna Maria Käkönen, Maija Wolf, Henri Sara, Matthias Nees, Olli Kallioniemi, Sirkku Pollari, Pekka Kohonen, Henrik Edgren, Theresa A. Guise, Institute for Molecular Medicine Finland, Research Programs Unit, and Genome-Scale Biology (GSB) Research Program

Subjects
Cancer Research, Pathology, AMINO-ACID TRANSPORTER, Osteoclasts, HORMONE-RELATED PROTEIN, NUCLEAR-FACTOR, THERAPY, Polymerase Chain Reaction, Metastasis, Mice, 0302 clinical medicine, Breast cancer, Serine, RNA, Small Interfering, l-serine, 0303 health sciences, Bone cancer, Bone metastasis, Cell Differentiation, Metastatic breast cancer, L-serine, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Osteoclast, Female, Breast disease, RECEPTOR ACTIVATOR, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Blotting, Western, BIOLOGY, Bone Neoplasms, Breast Neoplasms, Biology, Bone resorption, 03 medical and health sciences, OSTEOLYSIS, SDG 3 - Good Health and Well-being, Cell Line, Tumor, medicine, Animals, Humans, Bone Resorption, Phosphoglycerate Dehydrogenase, Transaminases, 030304 developmental biology, Cell Proliferation, Gene Expression Profiling, Cancer, Mammary Neoplasms, Experimental, IN-VITRO, medicine.disease, Phosphoric Monoester Hydrolases, Cancer research, SYSTEM, Neoplasm Transplantation
Abstract

This article has an erratum: http://dx.doi.org/10.1007/s10549-011-1654-4 Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, an understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidences for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDAMB- 231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.

Published
2009

7. Clues from hypercalcaemia

Author

Jonathan Waxman and Steve Nicholson

Subjects
musculoskeletal diseases, Male, medicine.medical_specialty, Cancer Research, Hypercalcaemia, Bone disease, Bone Neoplasms, HORMONE-RELATED PROTEIN, Biology, Bone resorption, Prostate cancer, Breast cancer, Osteoclast, Internal medicine, medicine, Biomarkers, Tumor, Humans, PEPTIDE, Oncology & Carcinogenesis, Neoplasm Metastasis, MALIGNANCY, Science & Technology, Parathyroid hormone-related protein, Parathyroid Hormone-Related Protein, Cancer, Prostatic Neoplasms, Proteins, medicine.disease, HUMORAL HYPERCALCEMIA, Prognosis, CANCER, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Endocrinology, Editorial, Oncology, Tumor Markers, Biological, Protein Biosynthesis, Cancer research, Hypercalcemia, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, hormones, hormone substitutes, and hormone antagonists
Abstract

The conundrum of hypercalcaemia in malignancy occurring in the absence of extensive bony metastases was finally solved in the late 1980s with the identification and cloning of PTHrP (parathyroid hormone-related protein) and the history of this discovery is summarised by Martin and Suva (1988). Original work in cell lines and a renal tumour was followed by the identification of PRHrP in a wide variety of malignances (Honda et al, 1988). PTHrP raises serum calcium and stimulates osteoclast activity, leading to bone destruction. This seemed to suggest a simple sequence of events, but malignancy, bony metastasis and hypercalcaemia are linked by mechanisms more subtle than any single linear chain of cause and effect. PTHrP shares eight of its first 13 amino acids with PTH (Mangin et al, 1988). This structural homology leads to shared receptor binding. There are biochemical differences in the effects of these two hormones. PTHrP is a more potent inhibitor of caliuria and promoter of phosphaturia than PTH. Circulating PTHrP is undetectable in health but present in around 80% of patients with humoral hypercalcaemia. Tissue expression of PTHrP is far more extensive than PTH, and this is reflected in a range of functions beyond calcium homeostasis (Strewler, 2000). The presence of PTHrP in the uterus and the stomach, coupled with its ability to relax smooth muscle, has led to the assertion that, in these tissues at least, it is PTHrP which is the true physiological effector molecule (Martin, 1996). The role of PTHrP in placental calcium transport seems, similarly, to imply far greater functional importance than that of PTH. It is the role of PTHrP in cartilage development, however, which may reveal its significance to the progression of malignant disease. When chondrocytes form new bone they first proliferate then produce the basic extracellular matrix which will be later invaded by cellular components of bone. The chondrocytes then apoptose. The absence of PTHrP, in PTHrP knock-out mice, leads to failure of proliferation and early apoptosis (Amizuka et al, 1996). This protection of chondrocytes from apoptosis in the physiological setting is mirrored in cancer, where transfection of PTHrP into cell lines confers resistance to apoptotic stimuli (Dougherty et al, 1999). PTHrP stimulates osteoclastic bone resorption. Studies in breast cancer have shown that PTHrP is expressed in most breast primaries and bony metastases, but to a lesser extent in visceral metastases (Powell et al, 1991). The question then arises whether PTHrP is not merely a marker for bony metastases but also prognostic factor for progression. Animal experiments using a PTHrP-expressing cell line and blocking monoclonal antibody have demonstrated the importance of PTHrP in progression to metastatic bone disease (Guise et al, 1996), while cell culture work indicates that PTHrP can function as a transforming growth factor. There is, then, a high index of suspicion in breast cancer that PTHrP is a key factor in the development of bony metastases. Prostate cancer has a different natural history to breast cancer. Hypercalcaemia is uncommon in prostate cancer and metastases are predominantly osteoblastic. It is important to realise, however, that the osteoblastic response seen in prostate cancer is preceded, at a cellular level, by osteoclast activation. The difference between breast and prostate, therefore, is not that osteoclast activation occurs or does not occur, but rather that in prostatic metastases an intense osteoblastic reaction is also present (Roodman, 2001). Elegant experiments using in vivo inocculation of paired transfected and untransfected cell lines have, furthermore, indicated a greater metastatic potential for the transfected lines (Rabbani et al, 1999) mirroring the results in breast cancer. The paper by Bryden et al. (2002) in this issue of the journal extends observations of PTHrP expression in other tumours to prostate cancer. The authors have demonstrated a high rate of concordance for the expression of both PTHrP and its receptor in paired primary tumours and bony metastases. The ultimate purpose of studies such as these is either to identify new markers of prognostic importance, or to provide a mechanistic explanation of disease progression which may yield new therapeutic targets. The high frequency of expression in primary prostate cancers would seem to indicate that PTHrP is a poor discriminator of metastatic potential. However, the sample sizes are small, and larger studies linking PTHrP expression to outcome are required to demonstrate any prognostic significance of this observation. The role of experimental therapeutics directed against PTHrP may seem nonsensical, since the numerous factors which come into play by the time metastatic bone disease has developed implies that there is no role for PTHrP-directed intervention. If, however, a link between PTHrP and progression to bone disease is established, then targetting the PTHrP at earlier disease stages might eventually lead to a change in the natural history of prostate cancer.

Published
2002

8. Calcitonin: characterisation and expression in a teleost fish, Fugu rubripes

Author

L. A. Bendell, Greg Elgar, Patricia M. Ingleton, Melody S. Clark, S. Warner, and Deborah M. Power

Subjects
Calcitonin, Brown trout, Salmon-calcitonin, Molecular Sequence Data, Gene Expression, Biology, Calcitonin gene-related peptide, Database, Exon, Endocrinology, Gene cluster, Sequence, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Gene-expression, Molecular Biology, In Situ Hybridization, Phylogeny, Genetics, Sequence Homology, Amino Acid, Reverse Transcriptase Polymerase Chain Reaction, Fugu, Gene Expression Profiling, Alternative splicing, fungi, Intron, Exons, Introns, Takifugu, Cell biology, Hormone-related protein, Pituitary, RNA splicing, Puffer fish, Rna, Takifugu niphobles
Abstract

The present report describes the structure and expression of the calcitonin gene in Fugu rubripes. It is composed of 4 exons and 3 introns. Splicing of exons 1, 2 and 3 generates the calcitonin pre-proprotein, while splicing of exons 1, 2 and 4 generates calcitonin gene-related protein (CGRP). Exons 1 and 2 encoding the signal sequence and the N-terminal peptide are common in both the gene products and this gene organisation has been conserved in human, rat, chicken and salmon. The gene environment around calcitonin in Fugu has been poorly conserved when compared with human, apart from a small gene cluster. The calcitonin gene in Fugu has a widespread tissue distribution but it is most highly expressed in the brain. The abundance of gene expression in the ultimobranchial gland and the pituitary indicates that these are important sites of production and that the peptide is probably secreted into the circulation and/or acts as a paracrine or autocrine controlling factor. Whilst the function of calcitonin in fish is still largely unknown, the distribution described here suggests that one of the potential functions may be as a neuropeptide. This work was supported by an MRC programme grant (MSC, GE), a Royal Society Joint Project grant (ESEP/JP) (MSC, DMP). DMP was funded by FCT, Portugal (BLS 58).

Published
2002

9. Long-term follow-up of two patients with metastatic neuroendocrine tumours treated with octreotide

Author

J. W. Sindram, JM Sepers, A.A. van de Loosdrecht, A.A. van Bodegraven, and University of Groningen

Subjects
ENDOCRINE PANCREATIC TUMORS, Pancreatic disease, paraprotein, medicine.medical_treatment, Paraproteinemias, Octreotide, HORMONE-RELATED PROTEIN, Gastroenterology, Metastasis, Duodenal Neoplasms, hemic and lymphatic diseases, Medicine, PEPTIDE, SOMATOSTATIN ANALOG, LOCALIZATION, Middle Aged, HUMORAL HYPERCALCEMIA, RECEPTORS, Neuroendocrine Tumors, Treatment Outcome, medicine.anatomical_structure, Somatostatin, Lymphatic Metastasis, Female, Pancreas, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Adult, medicine.medical_specialty, Hypercalcaemia, Antineoplastic Agents, Hormonal, Bone Neoplasms, DIAGNOSIS, Internal medicine, Internal Medicine, Humans, Chemotherapy, Parathyroid hormone-related protein, business.industry, parathyroid hormone-related protein, medicine.disease, ISLET-CELL TUMOR, Pancreatic Neoplasms, Endocrinology, Hypercalcemia, SCINTIGRAPHY, business, neuroendocrine neoplasia, octreotide, Follow-Up Studies
Abstract

Two patients are described with metastatic neuroendocrine tumours of the pancreas head and region of Vater. After surgery, administration of the long-acting somatostatin analogue octreotide was started. In the first patient we found an IgG-lambda paraproteinaemia and a parathyroid hormone-related protein (PTHrP) driven hypercalcaemia. By increasing the dose of octreotide the paraproteinaemia disappeared. In the second patient with a metastasized somatostatin producing neuroendocrine tumour, octreotide showed a long-term stabilizing effect on symptoms and progression of disease,The role of octreotide in the induction of changes in biological behaviour of malignant neuroendocrine cells is discussed. (C) 1998 Elsevier Science B.V. All rights reserved.

Published
1998

10. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author

William J. Tapper, Frederik Marmé, Natalia Bogdanova, Joe Dennis, Pei-Ei Wu, Vesa Kataja, Michael Jones, Dong-Young Noh, Xiaoqing Chen, Thilo Dörk, Javier Benitez, Arif B. Ekici, André G. Uitterlinden, Karin Leunen, Chen-Yang Shen, Esther M. John, Sune F. Nielsen, Adam M. Lee, Arto Mannermaa, Dieter Flesch-Janys, Diana Eccles, Don M. Conroy, Quinten Waisfisz, Sara Margolin, Hoda Anton-Culver, Peter Devilee, Ans M.W. van den Ouweland, Ruth Swann, Chia-Ni Hsiung, Peter Schürmann, Per Hall, Bertram Müller-Myhsok, Jonathan Beesley, Graham G. Giles, Qin Wang, Mitul Shah, Matthias W. Beckmann, Veli-Matti Kosma, Carmel Apicella, Henrik Flyger, Daniel F. Schmidt, Gianluca Severi, Kristen N. Stevens, Paolo Peterlongo, Helen Tsimiklis, Betül T. Yesilyurt, Irene L. Andrulis, Louiza S. Velentzis, Peter A. Fasching, Jyh-Cherng Yu, Caroline Baynes, Jenny Chang-Claude, Craig Luccarini, Leslie Bernstein, Katarzyna Durda, Antoinette Hollestelle, Catriona McLean, Georgia Chenevix-Trench, Rebecca Hein, Heli Nevanlinna, Arja Jukkola-Vuorinen, Jolanta Lissowska, Rita K. Schmutzler, Giuseppe Floris, Christa Stegmaier, David J. Hunter, Kristiina Aittomäki, Johann H. Karstens, Alan Ashworth, Alfons Meindl, Emilie Cordina-Duverger, Stefan Nickels, Julian Peto, Jan Lubinski, Børge G. Nordestgaard, Ed Dicks, Stig E. Bojesen, Christie J. van Asperen, Malcolm W.R. Reed, Michael J. Kerin, Annika Lindblom, Barbara Burwinkel, Kristy Driver, Darya Prokofieva, Montserrat Garcia-Closas, Thomas Brüning, Christina Justenhoven, Nazneen Rahman, Annegien Broeks, Hermann Brenner, Hiltrud Brauch, Laura Baglietto, Yuri I. Rogov, Clare Turnbull, A Jakubowska, Marina Bermisheva, Heiko Müller, Hanne Meijers-Heijboer, Anne-Lise Børrensen-Dale, Pascal Guénel, Stephen J. Chanock, Siranoush Manoukian, Melissa C. Southey, Daniel J. Park, M. Rosario Alonso, Christof Sohn, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Jonine D. Figueroa, Robert Winqvist, Jianjun Liu, Suthee Rattanamongkongul, Diether Lambrechts, Andreas Schneeweiss, Paul D.P. Pharoah, Alexander Miron, Ursula Eilber, Angela Cox, Anna González-Neira, Minh Bui, Frans B. L. Hogervorst, Peter Hillemanns, Peter Lichtner, Maartje J. Hooning, Roger L. Milne, Alison M. Dunning, Fernando Rivadeneira, Ian Tomlinson, Thérèse Truong, Volker Arndt, Rogier A. Oldenburg, Grethe I. Grenaker Alnæs, Senno Verhoef, Rob A. E. M. Tollenaar, Anna Marie Mulligan, Kenneth Muir, Christina Clarke Dur, Katarzyna Jaworska, Saila Kauppila, Olivia Fletcher, Jaana M. Hartikainen, Michael P. Lux, Kyriaki Michailidou, Stefano Fortuzzi, Douglas F. Easton, Anthony J. Swerdlow, Elza Khusnutdinova, Annie Perkins, Carl Blomqvist, Argyrios Ziogas, Keun-Young Yoo, Caroline Seynaeve, Natalia Antonenkova, Bruce A.J. Ponder, Vessela N. Kristensen, Gord Glendon, Daehee Kang, Elinor J. Sawyer, Michael Bremer, Louise A. Brinton, Minouk J. Schoemaker, Kamila Czene, Isabel dos Santos Silva, John L. Hopper, Astrid K. Irwanto, Nick Orr, S Gerty, Fergus J. Couch, Arkom Chaiwerawattana, Manjeet K. Humphreys, Marjanka K. Schmidt, Maya Ghoussaini, Nikki Graham, Artitaya Lophatananon, Florence Menegaux, Enes Makalic, Katri Pylkäs, Nichola Johnson, Xianshu Wang, Bernardo Bonanni, Mark Lathrop, Human genetics, CCA - Oncogenesis, Clinical Genetics, Internal Medicine, Medical Oncology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, and Human Genetics

Subjects
Candidate gene, Chromosomes,Human,Pair 21, analysis, cell carcinoma, Mammary gland, Estrogen receptor, Genome-wide association study, developmental regulatory molecule, 0302 clinical medicine, common variants, retinoic acid, Pair 12, genetics, hormone-related protein, Genetics, Chromosomes,Human,Pair 12, Treatment - Localised Therapies – Discovery and Development, Principal Component Analysis, 0303 health sciences, Bone metastasis, Single Nucleotide, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, epidemiology, Cancer Type - Breast Cancer, Female, Human, Risk, ulnar-mammary syndrome, parathyroid-hormone, European Continental Ancestry Group, Breast Neoplasms, Biology, Chromosomes, Polymorphism,Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Genetic predisposition, medicine, cancer, Humans, Women, Genetic Predisposition to Disease, Polymorphism, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], breast, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Cancer, confer susceptibility, medicine.disease, gene-expression, Logistic Models, negative-feedback, Genetic Loci, Cancer research, Other, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Pair 21, Meta-Analysis
Abstract

Item does not contain fulltext Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in approximately 70,000 cases and approximately 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Published
2012

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