title: 18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.
abstract: In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by positron emission tomography (PET) following i.v. injection of the glucose analogue (18)F-fluorodeoxy-glucose ((18)FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of (18)FDG retention, we interrogated the transcriptomes of human-cancer cell lines and primary tumors for metabolic pathways associated with (18)FDG radiotracer uptake. From ninety-five metabolic pathways that were interrogated, the glycolysis, and several glycolysis-related pathways (pentose phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This "FDG signature" predicted FDG uptake in breast cancer cell lines and overlapped with established gene expression signatures for the "basal-like" breast cancer subtype and MYC-induced tumorigenesis in mice. Human breast cancers with nuclear MYC staining and high RNA expression of MYC target genes showed high (18)FDG-PET uptake (P < 0.005). Presence of the FDG signature was similarly associated with MYC gene copy gain, increased MYC transcript levels, and elevated expression of metabolic MYC target genes in a human breast cancer genomic dataset. Together, our findings link clinical observations of glucose uptake with a pathologic and molecular subtype of human breast cancer. Furthermore, they suggest related approaches to derive molecular determinants of radiotracer retention for other PET-imaging probes.
authors.affiliation: Crump Institute for Molecular Imaging, University of California, Los Angeles, CA, USA.
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Palaskas
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Evangelia
authors.initials: E
authors.lastname: Komisopoulou
authors.forename: Justin
authors.initials: J
authors.lastname: Wong
authors.forename: Dan
authors.initials: D
authors.lastname: Rohle
authors.forename: Carl
authors.initials: C
authors.lastname: Campos
authors.forename: Nicolas
authors.initials: N
authors.lastname: Yannuzzi
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Osborne
authors.forename: Irina
authors.initials: I
authors.lastname: Linkov
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.forename: Richard
authors.initials: R
authors.lastname: Taschereau
authors.forename: Seema B
authors.initials: SB
authors.lastname: Plaisier
authors.forename: Chris
authors.initials: C
authors.lastname: Tran
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Michael E
authors.initials: ME
authors.lastname: Phelps
authors.forename: Cameron
authors.initials: C
authors.lastname: Brennan
authors.forename: Elisa
authors.initials: E
authors.lastname: Port
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics
chemical_list: D005462:Fluorine Radioisotopes; C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D005947:Glucose