title: Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations.
abstract: We hypothesized that cells bearing a single inherited "hit" in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. We report here on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations, which were validated independently by real-time reverse transcription-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings show that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of "one hit" represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Alfonso.Bellacosa@fccc.edu
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellacosa
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Suraj
authors.initials: S
authors.lastname: Peri
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.forename: Elena
authors.initials: E
authors.lastname: Caretti
authors.forename: Lisa
authors.initials: L
authors.lastname: Vanderveer
authors.forename: Betsy
authors.initials: B
authors.lastname: Bove
authors.forename: Carolyn
authors.initials: C
authors.lastname: Slater
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Mary
authors.initials: M
authors.lastname: Daly
authors.forename: Sharon
authors.initials: S
authors.lastname: Howard
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Yeung
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
authors.forename: James A
authors.initials: JA
authors.lastname: Crowell
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Eric
authors.initials: E
authors.lastname: Ross
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Alfred G
authors.initials: AG
authors.lastname: Knudson
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001940:Breast; D057225:Data Mining; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger