title: Proteomics of genetically engineered mouse mammary tumors identifies fatty acid metabolism members as potential predictive markers for cisplatin resistance.
abstract: In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset (Brca1) gene. The proteome of cisplatin-sensitive BRCA1-deficient mammary tumors was compared with that of cisplatin-resistant mammary tumors resembling pleomorphic invasive lobular carcinoma. The analyses were performed 24 h after administration of the maximum tolerable dose of cisplatin. At this time point, drug-sensitive BRCA1-deficient tumors showed DNA damage, but cells were largely viable. By applying paired statistics and quantitative filtering, we identified highly discriminatory markers for the sensitive and resistant model. Proteins up-regulated in the sensitive model are involved in centrosome organization, chromosome condensation, homology-directed DNA repair, and nucleotide metabolism. Major discriminatory markers that were up-regulated in the resistant model were predominantly involved in fatty acid metabolism, such as fatty-acid synthase. Specific inhibition of fatty-acid synthase sensitized resistant cells to cisplatin. Our data suggest that exploring the functional link between the DNA damage response and cancer metabolism shortly after the initial treatment may be a useful strategy to predict the efficacy of cisplatin.
authors: OncoProteomics Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors: Marc
authors: M
authors: Warmoes
authors: Janneke E
authors: JE
authors: Jaspers
authors: Guotai
authors: G
authors: Xu
authors: Bharath K
authors: BK
authors: Sampadi
authors: Thang V
authors: TV
authors: Pham
authors: Jaco C
authors: JC
authors: Knol
authors: Sander R
authors: SR
authors: Piersma
authors: Epie
authors: E
authors: Boven
authors: Jos
authors: J
authors: Jonkers
authors: Sven
authors: S
authors: Rottenberg
authors: Connie R
authors: CR
authors: Jimenez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D053898:Biosynthetic Pathways; D064200:Cdh1 Proteins / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D055785:Gene Knockdown Techniques; D019398:Genes, BRCA1; D016158:Genes, p53; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D064200:Cdh1 Proteins; D005227:Fatty Acids; C577585:Fzr1 protein, mouse; D020543:Proteome; D054890:Fatty Acid Synthase, Type I; D002945:Cisplatin
references: Anal Chem. 2002 Oct 15;74(20):5383-92
references: 12403597
references: J Med Chem. 2012 Jun 14;55(11):5013-23
references: 22559865
references: Exp Cell Res. 2012 May 1;318(8):877-86
references: 22507175
references: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12111-6
references: 17626182
references: Ann Oncol. 2011 Jul;22(7):1561-1570
references: 21135055
references: Genome Res. 2003 Nov;13(11):2498-504
references: 14597658
references: Mol Cell Proteomics. 2010 May;9(5):988-1005
references: 20089989
references: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references: 20100965
references: Clin Cancer Res. 2010 Dec 15;16(24):6159-68
references: 20802015
references: Int J Oncol. 2011 Feb;38(2):537-46
references: 21170507
references: Cancer Cell. 2006 Nov;10(5):437-49
references: 17097565
references: Nat Rev Drug Discov. 2008 Jun;7(6):489-503
references: 18511927
references: Bioinformatics. 2010 Feb 1;26(3):363-9
references: 20007255
references: Future Oncol. 2010 Apr;6(4):551-62
references: 20373869
references: J Clin Endocrinol Metab. 2008 Oct;93(10):4088-97
references: 18682509
references: Cell Cycle. 2010 Dec 15;9(24):4836-40
references: 21150277
references: Mol Syst Biol. 2007;3:89
references: 17353931
references: Bioinformatics. 2012 Sep 15;28(18):i596-i602
references: 22962487
references: Cell Cycle. 2008 May 15;7(10):1353-9
references: 18418074
references: Cancer Cell. 2011 Sep 13;20(3):370-83
references: 21907927
references: Cell. 2009 Mar 20;136(6):1056-72
references: 19303849
references: Mol Med. 2011;17(7-8):635-45
references: 21442130
references: Mol Cancer Ther. 2010 May;9(5):1244-55
references: 20423996
references: Nat Med. 2011 Oct 30;17(11):1498-503
references: 22037646
references: Int J Oncol. 2010 May;36(5):1309-14
references: 20372807
references: Nat Methods. 2012 Mar 18;9(5):471-2
references: 22426491
references: J Biol Chem. 2012 Feb 24;287(9):6764-72
references: 22219182
references: Cell Prolif. 2008 Feb;41(1):59-85
references: 18211286
references: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12117-22
references: 17626183
references: Nat Biotechnol. 2008 Dec;26(12):1367-72
references: 19029910
references: Mol Carcinog. 2008 Feb;47(2):157-63
references: 17620310
references: Breast Cancer Res. 2011;13(6):R131
references: 22177475
references: Lab Invest. 2011 Feb;91(2):232-40
references: 20805790
references: Int J Cancer. 2008 Dec 1;123(11):2557-65
references: 18770866
references: Oncol Rep. 2007 Oct;18(4):973-80
references: 17786362
references: J Med Chem. 2011 Dec 22;54(24):8574-81
references: 22085405
references: Bioinformatics. 2005 Aug 15;21(16):3448-9
references: 15972284
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D561-8
references: 21045058
references: Dis Model Mech. 2011 May;4(3):347-58
references: 21282721
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84
references: 18971340
references: Anal Chem. 2003 Sep 1;75(17):4646-58
references: 14632076
references: Clin Cancer Res. 2009 Dec 15;15(24):7608-7615
references: 20008854
references: Nat Rev Cancer. 2011 Dec 23;12(1):68-78
references: 22193408
references: Nat Rev Cancer. 2011 Jun 24;11(7):467-80
references: 21701511
references: Mol Cell Proteomics. 2012 Jul;11(7):M111.013334
references: 22366898
references: J Clin Oncol. 2005 Jan 1;23(1):41-8
references: 15625359
references: Oncogene. 2012 Apr 12;31(15):1869-83
references: 21892204