Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations.
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.
Bellacosa
Alfonso
A
Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Alfonso.Bellacosa@fccc.edu
Godwin
Andrew K
AK
Peri
Suraj
S
Devarajan
Karthik
K
Caretti
Elena
E
Vanderveer
Lisa
L
Bove
Betsy
B
Slater
Carolyn
C
Zhou
Yan
Y
Daly
Mary
M
Howard
Sharon
S
Campbell
Kerry S
KS
Nicolas
Emmanuelle
E
Yeung
Anthony T
AT
Clapper
Margie L
ML
Crowell
James A
JA
Lynch
Henry T
HT
Ross
Eric
E
Kopelovich
Levy
L
Knudson
Alfred G
AG
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
D014408:Biomarkers, Tumor; D012333:RNA, Messenger