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1. Additional file 7 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 7: Fig. S5. Effect of PD-L1 and MT Oas2 on primary tumor initiation and expansion in parous mice. Examples of tumor growth curves of individual mice. The 2nd/3rd and 4th mammary glands were palpated twice weekly and tumor growth was estimated by measurement of the major and minor axis of individual tumors using calipers. Y axis is placed at the day of tumor detection on the x axis as day 0. Black diamonds show a treatment with IP IgG or PD-L1 antibodies and red diamonds indicate parity. WT = wild type, MT = MT Oas2 MT/MT = homozygous MT Oas2.

Published
2022
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2. Additional file 8 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 8: Fig. S6. Effect of PD-L1 and MT Oas2 on primary tumor initiation and expansion in parous mice. Two-way Kaplan–Meier survival analysis for the indicated periods and endpoints, and for the indicated genotypes and treatments (PD-L1 or IgG IP), of mouse cohorts. P values and hazard ratios (HR) calculated by the log-rank test using GraphPad Prism. n = 8 WT PD-L1, 8 WT IgG, 14 MT PD-L1, 15 MT IgG.

Published
2022
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3. Additional file 6 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 6: Fig. S4. Flow cytometry gating strategy for monocytes and neutrophils known as myeloid-derived suppressor cells. Series of gates used to quantify monocytes and neutrophils using flow cytometry.

Published
2022
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4. Additional file 5 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 5: Fig. S3. Effects of MT Oas2 on T cells in parous mice. A screening of various T-cell parameters was undertaken in mammary tumors, lymph nodes, spleen and thymus. Error bars are standard error of the mean and p values calculated by Student’s t test (all non-significant). Axes represent % of total cells passing the previous gate. Genotypes, WT/WT homozygous wildtype Oas2, MT/MT homozygous mutant Oas2.

Published
2022
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5. Additional file 1 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 1: Table S1. Antibodies, concentration and antigen retrieval conditions for immunohistochemistry. All reagents were from Leica BOND or DAKO for automated or manual IHC (as specified). Visualization of antigen–antibody complexes was performed using the DAB + liquid substrate chromogen system (K3467).

Published
2022
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6. Additional file 3 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 3: Fig. S1. Effect of MT Oas2 on primary tumor expansion in parous mice. Examples of tumor growth curves of individual mice. The left- and right-hand side 2nd/3rd and 4th mammary glands were palpated twice weekly and tumor growth was estimated by measurement of the major and minor axis of each gland using calipers. Y axis is placed at parity indicated on the x axis as day 0. Numbers show the total number of glands with tumors detected, the number that showed a period of no growth, and the number that showed regression at or following parity. W, wild type; M, MT; W/W, homozygous wild type; M/M, homozygous MT.

Published
2022
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7. Additional file 4 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Subjects
reproductive and urinary physiology
Abstract

Additional file 4: Fig. S2. Effect of MT Oas2 on primary tumor initiation and expansion in nulliparous and parous mice. Two-way Kaplan–Meier survival analysis for the indicated periods and endpoints, and for the indicated genotypes, WT wildtype Oas2, MT mutant Oas2, and parity status of mouse cohorts (20 per group). P values and hazard ratios (HR) calculated by the log-rank test using GraphPad Prism. n = 19 MT parous, 21 WT parous, 20 MT nulliparous and 19 WT nulliparous.)

Published
2022
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8. Additional file 2 of Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Author

Ho, Wing-Hong Jonathan, Law, Andrew M. K., Masle-Farquhar, Etienne, Castillo, Lesley E., Mawson, Amanda, O’Bryan, Moira K., Goodnow, Christopher C., Gallego-Ortega, David, Oakes, Samantha R., and Ormandy, Christopher J.

Abstract

Additional file 2: Table S2. Antibodies used for flow cytometry. Panel name, antibody name by antigen recognized and conjugated fluorochrome, the antibody supplier and catalogue number and final diluted concentration for each is shown.

Published
2022
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10. Alpha anticholine kinase monoclonal antibodies and their use in analytical techniques for the diagnosis of cancer and the preparation of medicinal products

Author

Ramírez de Molina, Ana, Gallego Ortega, David, and Lacal, Juan Carlos

Abstract

Fecha de solicitud: 06/12/2007.- Titular: Consejo Superior de Investigaciones Científicas (CSIC), Alpha anticholine kinase monoclonal antibodies and their use in analytical techniques for the diagnosis of cancer and the preparation of medicinal products. The monoclonal antibodies AD1, AD2, AD3, AD4, AD5, AD6, AD7, AD8, AD9, AD10, AD11, AD12, AD13 and AD14 are highly specific and recognize human alpha choline kinase protein (ChoKa) with high sensitivity. This means that they can be used for the detection and/or quantification of this protein in any type of sample, including biological samples. In particular they allow the development of in vitro methods for cancer diagnosis, prognosis and/or monitoring of cancer progress or evaluating anti-cancer treatments in which the level of ChoKa expression is determined through one or more of the monoclonal antibodies of the invention or kits comprising them.; In addition to this, AD3, AD8 and AD13, which interfere with the choline kinase activity of ChoKa, can be used for the preparation of medicinal products against cancer., Anticuerpos monoclonales de la quinasa del anticholine de la alfa y su uso en las técnicas analíticas para el diagnóstico del cáncer y la preparación de medicamentos. El son AD1, AD2, AD3, AD4, AD5, AD6, AD7, AD8, AD9, AD10, AD11, AD12, AD13 y AD14 de los anticuerpos monoclonales altamente específico y reconoce la proteína humana de la quinasa de la colina de la alfa (ChoKa) con alta sensibilidad. Esto significa que bote sean utilizados para la detección y/o la cuantificación de esta proteína en cualquier tipo de muestra, incluyendo muestras biológicas. Particularmente permiten el desarrollo de los métodos ines vitro para el diagnóstico, el pronóstico y/o el control del progreso del cáncer o evaluar del cáncer los tratamientos anticáncer en los cuales el nivel de expresión de ChoKa se determina con uno o más de los anticuerpos monoclonales de la invención o de los estuches comprendiendolos. Además de esto, de AD3, de AD8 y de AD13, que interfieren con la actividad de la quinasa de la colina de ChoKa, el bote sea utilizado para la preparación de medicamentos contra cáncer.

Published
2007

11. Método in vitro para identificar compuestos para terapia del cáncer

Author

Lacal, Juan Carlos, Ramírez de Molina, Ana, Gallego Ortega, David, and Báñez Coronel, Mónica

Subjects
Patente, Terapias contra el cáncer
Abstract

La presente invención se refiere a un método para identificar y evaluar la eficacia de compuestos para la terapia del cáncer, especialmente para el cáncer de pulmón, de mama o colorrectal, con el fin de desarrollar nuevos medicamentos; así como agentes que inhiben la expresión y/o la actividad de la proteína Colina Quinasa Alfa, y/o los efectos de esta expresión., Consejo Superior de Investigaciones Científicas (España), T3 Traducción de patente europea

Published
2005

12. Additional file 1: of MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib

Author

Young, Adelaide I. J., Law, Andrew, Castillo, Lesley, Chong, Sabrina, Cullen, Hayley, Koehler, Martin, Herzog, Sebastian, Brummer, Tilman, Erinna Lee, Fairlie, Walter, Morghan Lucas, Herrmann, David, Allam, Amr, Timpson, Paul, D. Watkins, Millar, Ewan, O’Toole, Sandra, Gallego-Ortega, David, Ormandy, Christopher, and Oakes, Samantha

Subjects
3. Good health
Abstract

showing supplementary materials and methods. (DOCX 31Â kb)

13. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author

Figlioli, Gisella, Bogliolo, Massimo, Catucci, Irene, Caleca, Laura, Lasheras, Sandra Viz, Pujol, Roser, Kiiski, Johanna I., Muranen, Taru A., Barnes, Daniel R., Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K., Leslie, Goska, Aalfs, Cora M., Adank, Muriel A., Adlard, Julian, Agata, Simona, Cadoo, Karen, Agnarsson, Bjarni A., Ahearn, Thomas, Aittomäki, Kristiina, Ambrosone, Christine B., Andrews, Lesley, Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Asseryanis, Ella, Auber, Bernd, Auvinen, Päivi, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Barwell, Julian, Beane Freeman, Laura E., Beauparlant, Charles Joly, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Berger, Raanan, Bermisheva, Marina, Blanco, Amie M., Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brady, Angela F., Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campa, Daniele, Campbell, Ian G., Canzian, Federico, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Claes, Kathleen B. M., Clarke, Christine L., Collavoli, Anita, Conner, Thomas A., Cox, David G., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S., Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Dos-Santos-Silva, Isabel, Durda, Katarzyna, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Foulkes, William D., Friebel, Tara M., Friedman, Eitan, Gabrielson, Marike, Gaddam, Pragna, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., Guénel, Pascal, Gutierrez-Barrera, Angelica M., Haeberle, Lothar, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hopper, John L., Hosgood, H. Dean, Howell, Anthony, Hu, Chunling, Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M., Jones, Michael E., Jung, Audrey, Kaaks, Rudolf, Karlan, Beth Y., Khusnutdinova, Elza, Kitahara, Cari M., Konstantopoulou, Irene, Koutros, Stella, Kraft, Peter, Lambrechts, Diether, Lazaro, Conxi, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lilyquist, Jenna, Loud, Jennifer T., Lu, Karen H., Luben, Robert N., Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Maurer, Tabea, Mavroudis, Dimitrios, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Newman, William G., Nguyen-Dumont, Tu, Nielsen, Finn Cilius, Nielsen, Sarah, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Osorio, Ana, Ottini, Laura, Peissel, Bernard, Peixoto, Ana, Peto, Julian, Plaseska-Karanfilska, Dijana, Pocza, Timea, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Rack, Brigitte, Rantala, Johanna, Rashid, Muhammad U., Rau-Murthy, Rohini, Rennert, Gad, Lejbkowicz, Flavio, Rhenius, Valerie, Romero, Atocha, Rookus, Matti A., Ross, Eric A., Rossing, Maria, Rudaitis, Vilius, Ruebner, Matthias, Saloustros, Emmanouil, Sanden, Kristin, Santamariña, Marta, Scheuner, Maren T., Schmutzler, Rita K., Schneider, Michael, Scott, Christopher, Senter, Leigha, Shah, Mitul, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F., Sohn, Christof, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steele, Linda, Stoppa-Lyonnet, Dominique, Tapper, William J., Teixeira, Manuel R., Terry, Mary Beth, Thomassen, Mads, Thompson, Jennifer, Thull, Darcy L., Tischkowitz, Marc, Tollenaar, Rob A.E.M., Torres, Diana, Troester, Melissa A., Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M., Van Rensburg, Elizabeth J., Van Veen, Elke M., Vega, Ana, Viel, Alessandra, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Wendt, Camilla, Wieme, Greet, Wolk, Alicja, Yang, Xiaohong R., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Dunning, Alison M., Lush, Michael, Wang, Qin, McGuffog, Lesley, Parsons, Michael T., Pharoah, Paul D. P., Fostira, Florentia, Toland, Amanda E., Andrulis, Irene L., Ramus, Susan J., Swerdlow, Anthony J., Greene, Mark H., Chung, Wendy K., Milne, Roger L., Chenevix-Trench, Georgia, Dörk, Thilo, Schmidt, Marjanka K., Easton, Douglas F., Radice, Paolo, Hahnen, Eric, Antoniou, Antonis C., Couch, Fergus J., Nevanlinna, Heli, Surrallés, Jordi, Peterlongo, Paolo, Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Belotti, Muriel, Bertrand, Ophélie, Birot, Anne-Marie, Buecher, Bruno, Caputo, Sandrine, Dupré, Anaïs, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Le Mentec, Marine, Moncoutier, Virginie, De Pauw, Antoine, Saule, Claire, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Léone, Mélanie, Bressac-De-Paillerets, Brigitte, Caron, Olivier, Guillaud-Bataille, Marine, Bignon, Yves-Jean, Uhrhammer, Nancy, Bonadona, Valérie, Lasset, Christine, Berthet, Pascaline, Castera, Laurent, Vaur, Dominique, Bourdon, Violaine, Noguès, Catherine, Noguchi, Tetsuro, Popovici, Cornel, Remenieras, Audrey, Sobol, Hagay, Coupier, Isabelle, Pujol, Pascal, Adenis, Claude, Dumont, Aurélie, Révillion, Françoise, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Longy, Michel, Sevenet, Nicolas, Gladieff, Laurence, Guimbaud, Rosine, Feillel, Viviane, Toulas, Christine, Dreyfus, Hélène, Leroux, Christine Dominique, Peysselon, Magalie, Rebischung, Christine, Legrand, Clémentine, Baurand, Amandine, Bertolone, Geoffrey, Coron, Fanny, Faivre, Laurence, Jacquot, Caroline, Lizard, Sarab, Kientz, Caroline, Lebrun, Marine, Prieur, Fabienne, Fert-Ferrer, Sandra, Mari, Véronique, Vénat-Bouvet, Laurence, Bézieau, Stéphane, Delnatte, Capucine, Mortemousque, Isabelle, Colas, Chrystelle, Coulet, Florence, Soubrier, Florent, Warcoin, Mathilde, Bronner, Myriam, Sokolowska, Johanna, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Manouvrier-Hanu, Sylvie, Lejeune, Sophie, Aghmesheh, Morteza, Greening, Sian, Amor, David, Gattas, Mike, Botes, Leon, Buckley, Michael, Friedlander, Michael, Koehler, Jessica, Meiser, Bettina, Saleh, Mona, Salisbury, Elizabeth, Trainer, Alison, Tucker, Kathy, Antill, Yoland, Dobrovic, Alexander, Fellows, Andrew, Fox, Stephen, Harris, Marion, Nightingale, Sophie, Phillips, Kelly, Sambrook, Joe, Thorne, Heather, Armitage, Shane, Arnold, Leanne, Kefford, Rick, Kirk, Judy, Rickard, Edwina, Bastick, Patti, Beesley, Jonathan, Hayward, Nick, Spurdle, Amanda, Walker, Logan, Beilby, John, Saunders, Christobel, Bennett, Ian, Blackburn, Anneke, Bogwitz, Michael, Gaff, Clara, Lindeman, Geoff, Pachter, Nick, Scott, Clare, Sexton, Adrienne, Visvader, Jane, Taylor, Jessica, Winship, Ingrid, Brennan, Meagan, Brown, Melissa, French, Juliet, Edwards, Stacey, Burgess, Matthew, Burke, Jo, Patterson, Briony, Butow, Phyllis, Culling, Bronwyn, Caldon, Liz, Callen, David, Chauhan, Deepa, Eisenbruch, Maurice, Heiniger, Louise, Chauhan, Manisha, Christian, Alice, Dixon, Joanne, Kidd, Alexa, Cohen, Paul, Colley, Alison, Fenton, Georgina, Crook, Ashley, Dickson, Rebecca, Field, Michael, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dudding, Tracy, Edkins, Ted, Farshid, Gelareh, Flanagan, James, Fong, Peter, Forrest, Laura, Gallego-Ortega, David, George, Peter, Gill, Grantley, Kollias, James, Haan, Eric, Hart, Stewart, Jenkins, Mark, Hunt, Clare, Lakhani, Sunil, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, O’Connell, Shona, O’Sullivan, Sarah, Pieper, Ellen, Robinson, Bridget, Saunus, Jodi, Scott, Elizabeth, Shelling, Andrew, Williams, Rachael, and Young, Mary Ann

Subjects
692/4028/67/68, 631/67/68, article, nutritional and metabolic diseases, 631/208/68, skin and connective tissue diseases, 3. Good health
Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

14. Additional file 1: of MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib

Author

Young, Adelaide I. J., Law, Andrew, Castillo, Lesley, Chong, Sabrina, Cullen, Hayley, Koehler, Martin, Herzog, Sebastian, Brummer, Tilman, Erinna Lee, Fairlie, Walter, Morghan Lucas, Herrmann, David, Allam, Amr, Timpson, Paul, D. Watkins, Millar, Ewan, O’Toole, Sandra, Gallego-Ortega, David, Ormandy, Christopher, and Oakes, Samantha

Subjects
3. Good health
Abstract

showing supplementary materials and methods. (DOCX 31Â kb)

15. ALTEN: A High-Fidelity Primary Tissue-Engineering Platform to Assess Cellular Responses Ex Vivo

Author

Andrew M. K. Law, Jiamin Chen, Yolanda Colino‐Sanguino, Laura Rodriguez de la Fuente, Guocheng Fang, Susan M. Grimes, Hongxu Lu, Robert J. Huang, Sarah T. Boyle, Jeron Venhuizen, Lesley Castillo, Javad Tavakoli, Joanna N. Skhinas, Ewan K. A. Millar, Julia Beretov, Fernando J. Rossello, Joanne L. Tipper, Christopher J. Ormandy, Michael S. Samuel, Thomas R. Cox, Luciano Martelotto, Dayong Jin, Fatima Valdes‐Mora, Hanlee P. Ji, David Gallego‐Ortega, Law, Andres MK, Chen, Jiamin, Colino-Sanguino, Yolanda, Fuente, Laura Rodreguez de la, Boyle, Sarah T, Samuel, Michael S, and Gallego-Ortega, David

Subjects
Tissue Engineering, Alginates, General Chemical Engineering, General Engineering, General Physics and Astronomy, Medicine (miscellaneous), Cell Communication, tissue microenvironment, Biochemistry, Genetics and Molecular Biology (miscellaneous), three dimensional culture, Biomimetics, single-cell RNAseq, Lab-On-A-Chip Devices, ex vivo drug screening, alginate, General Materials Science, whole-tissue organoids
Abstract

To fully investigate cellular responses to stimuli and perturbations within tissues, it is essential to replicate the complex molecular interactions within the local microenvironment of cellular niches. Here, the authors introduce Alginate-based tissue engineering (ALTEN), a biomimetic tissue platform that allows ex vivo analysis of explanted tissue biopsies. This method preserves the original characteristics of the source tissue's cellular milieu, allowing multiple and diverse cell types to be maintained over an extended period of time. As a result, ALTEN enables rapid and faithful characterization of perturbations across specific cell types within a tissue. Importantly, using single-cell genomics, this approach provides integrated cellular responses at the resolution of individual cells. ALTEN is a powerful tool for the analysis of cellular responses upon exposure to cytotoxic agents and immunomodulators. Additionally, ALTEN's scalability using automated microfluidic devices for tissue encapsulation and subsequent transport, to enable centralized high-throughput analysis of samples gathered by large-scale multicenter studies, is shown Refereed/Peer-reviewed

Published
2022

16. ELF5 modulates the estrogen receptor cistrome in breast cancer

Author

Mark P. Molloy, Andrew M. K. Law, Alexander Swarbrick, David Gallego-Ortega, Nenad Bartonicek, Maria Kalyuga, Jason S. Carroll, Christopher J. Ormandy, Daniel L. Roden, Susan J. Clark, Warren Kaplan, Catherine L. Piggin, Christoph Krisp, Samantha R. Oakes, Matthew J. Naylor, Law, Andrew MK [0000-0002-7492-114X], Swarbrick, Alexander [0000-0002-3051-5676], Oakes, Samantha R [0000-0003-1838-2310], Gallego-Ortega, David [0000-0002-2347-7835], Carroll, Jason S [0000-0003-3643-0080], Bartonicek, Nenad [0000-0003-2144-1887], Ormandy, Christopher J [0000-0002-2504-7919], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, Cancer Treatment, Estrogen receptor, Gene Expression, QH426-470, Biochemistry, Database and Informatics Methods, Binding Analysis, Mice, 0302 clinical medicine, Gene expression, Breast Tumors, Medicine and Health Sciences, Genetics (clinical), Regulation of gene expression, 0303 health sciences, Brain Neoplasms, ETS transcription factor family, Endocrine Therapy, 3. Good health, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, Cistrome, Oncology, Receptors, Estrogen, MCF-7 Cells, Female, Sequence Analysis, Research Article, Protein Binding, Hepatocyte Nuclear Factor 3-alpha, Bioinformatics, DNA transcription, Breast Neoplasms, Biology, Research and Analysis Methods, 03 medical and health sciences, Sequence Motif Analysis, Breast Cancer, Genetics, Animals, Humans, Gene Regulation, Enhancer, Molecular Biology, Transcription factor, Ecology, Evolution, Behavior and Systematics, Chemical Characterization, 030304 developmental biology, Biology and Life Sciences, Proteins, Cancers and Neoplasms, Estrogens, Hormones, Regulatory Proteins, FOXA1, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance., Author summary Two thirds of breast cancers are initially treated with endocrine therapy because they are likely to rely on estrogen for their proliferation. Understanding why this therapy ultimately fails in 2/3 of cases offers the chance of durable treatment. In 2012 we hypothesised that normal developmental cell fate decisions taken by mammary progenitor cells persist in tumours that are maintained by instances of a cancerous progenitor, and that a change in the relative influence of the two major transcription factors that drive progenitor cell fate, ER to specify the hormone sensing lineage, and ELF5 to specify the ER- alveolar lineage, may allow a cancer to shift control of proliferation from estrogen to ELF5. Here we show that these transcription factors are often co located at super enhancers, enhancers and at the promoters of differentially regulated genes. When the levels of ELF5 were increased this caused ER and its pioneer factor FOXA1 to move to new regions of the genome associated with resistance to hormonal therapy. We also showed that ELF both regulated and bound directly to members of the ER-transcriptional complex. These findings provide the first indication of the mechanisms by which an increase in ELF5 could drive the acquisition of endocrine resistance.

Published
2020

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