Myriem Boufraqech1, Dhaval Patel1, Naris Nilubol1, Astin Powers2, Timothy King1, Jasmine Shell1, Justin Lack3,4, Lisa Zhang1, Sudheer Kumar Gara1, Viswanath Gunda5, Joanna Klubo-Gwiezdzinska6, Suresh Kumar1, James Fagin7, Jeffrey Knauf7, Sareh Parangi5, David Venzon8, Martha Quezado2, Electron Kebebew9. 1. 1 Endocrine Oncology Branch, Endocrinology, and Obesity Branch, National Institutes of Health, Bethesda, Maryland. 2. 2 Laboratory of Pathology, National Institutes of Health, Bethesda, Maryland. 3. 3 NIAID Collaborative Bioinformatics Resource (NCBR), NIAID, NIH, Bethesda, Maryland. 4. 4 Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland. 5. 5 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 6. 6 Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. 7. 7 Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. 8. 8 Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 9. 9 Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, California.
Abstract
BACKGROUND: The BRAFV600E mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF-mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective was to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer. METHODS: The prognostic value of LOX and its association with mutated BRAF was analyzed in The Cancer Genome Atlas and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of mutant BRAF and mouse models of BRAFV600E were used to test the effect on LOX expression. RESULTS: In The Cancer Genome Atlas cohort, LOX expression was higher in BRAF-mutant tumors compared to wild-type tumors (p < 0.0001). Patients with BRAF-mutant tumors with high LOX expression had a shorter disease-free survival (p = 0.03) compared to patients with a BRAF mutation and the low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter disease-free survival (p = 0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely, overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E showed strong LOX and p-ERK expression in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expression. CONCLUSIONS: The data suggest that BRAFV600E tumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression.
BACKGROUND: The BRAFV600E mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF-mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective was to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer. METHODS: The prognostic value of LOX and its association with mutated BRAF was analyzed in The Cancer Genome Atlas and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of mutant BRAF and mouse models of BRAFV600E were used to test the effect on LOX expression. RESULTS: In The Cancer Genome Atlas cohort, LOX expression was higher in BRAF-mutant tumors compared to wild-type tumors (p < 0.0001). Patients with BRAF-mutant tumors with high LOX expression had a shorter disease-free survival (p = 0.03) compared to patients with a BRAF mutation and the low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter disease-free survival (p = 0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely, overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E showed strong LOX and p-ERK expression in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expression. CONCLUSIONS: The data suggest that BRAFV600Etumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression.
Authors: Matthew A Nehs; Carmelo Nucera; Sushruta S Nagarkatti; Peter M Sadow; Dieter Morales-Garcia; Richard A Hodin; Sareh Parangi Journal: Endocrinology Date: 2011-12-27 Impact factor: 4.736
Authors: G Riesco-Eizaguirre; P Gutiérrez-Martínez; M A García-Cabezas; M Nistal; P Santisteban Journal: Endocr Relat Cancer Date: 2006-03 Impact factor: 5.678
Authors: Chong-Feng Gao; Qian Xie; Yan-Li Su; Julie Koeman; Sok Kean Khoo; Margaret Gustafson; Beatrice S Knudsen; Rick Hay; Nariyoshi Shinomiya; George F Vande Woude Journal: Proc Natl Acad Sci U S A Date: 2005-07-15 Impact factor: 11.205
Authors: Florian A Karreth; Markus Reschke; Anna Ruocco; Christopher Ng; Bjoern Chapuy; Valentine Léopold; Marcela Sjoberg; Thomas M Keane; Akanksha Verma; Ugo Ala; Yvonne Tay; David Wu; Nina Seitzer; Martin Del Castillo Velasco-Herrera; Anne Bothmer; Jacqueline Fung; Fernanda Langellotto; Scott J Rodig; Olivier Elemento; Margaret A Shipp; David J Adams; Roberto Chiarle; Pier Paolo Pandolfi Journal: Cell Date: 2015-04-02 Impact factor: 41.582
Authors: Aime T Franco; Roberta Malaguarnera; Samuel Refetoff; Xiao-Hui Liao; Emma Lundsmith; Shioko Kimura; Catrin Pritchard; Richard Marais; Terry F Davies; Lee S Weinstein; Min Chen; Neal Rosen; Ronald Ghossein; Jeffrey A Knauf; James A Fagin Journal: Proc Natl Acad Sci U S A Date: 2011-01-10 Impact factor: 11.205
Authors: Alison Gartland; Janine T Erler; Thomas R Cox; Robin M H Rumney; Erwin M Schoof; Lara Perryman; Anette M Høye; Ankita Agrawal; Demelza Bird; Norain Ab Latif; Hamish Forrest; Holly R Evans; Iain D Huggins; Georgina Lang; Rune Linding Journal: Nature Date: 2015-05-27 Impact factor: 49.962
Authors: Bryan W Miller; Jennifer P Morton; Mark Pinese; Grazia Saturno; Nigel B Jamieson; Ewan McGhee; Paul Timpson; Joshua Leach; Lynn McGarry; Emma Shanks; Peter Bailey; David Chang; Karin Oien; Saadia Karim; Amy Au; Colin Steele; Christopher Ross Carter; Colin McKay; Kurt Anderson; Thomas R Jeffry Evans; Richard Marais; Caroline Springer; Andrew Biankin; Janine T Erler; Owen J Sansom Journal: EMBO Mol Med Date: 2015-08 Impact factor: 12.137