title: A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers.
abstract: Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Brittney-Shea
authors.initials: BS
authors.lastname: Herbert
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Chanoux
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.|Division of Biostatistics, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Baenziger
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Chirayu P
authors.initials: CP
authors.lastname: Goswami
authors.affiliation: Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jeanette N
authors.initials: JN
authors.lastname: McClintick
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Pennington
authors.affiliation: Departments of Medicine and Genetic Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
mesh_terms: D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D057895:Haploinsufficiency; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D001372:Aza Compounds; D014408:Biomarkers, Tumor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009363:Neoplasm Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one; C402665:CP 31398