Altered gene expression in normal breast and ovarian epithelial cells from BRCA1 and BRCA2 mutation carriers

Early genetic changes during cancer initiation may provide targets for agents that delay, or even prevent, cancer. 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. Here, we report 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 that were independently validated by real-time RT-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 demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner, and that 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 Using affymetrix U133 plus2 chips, we compare the transcriptome of primary breast and ovarian epithelial cultures derived from subjects predisposed to cancer, bearing monoallelic BRCA1 or BRCA2 mutations, with corresponding cultures from control individuals that do not have mutations. For both breast and ovarian samples, epithelial cell cultures were generated from 6 subjects that have both BRCA1 or BRCA2 mutations and 6 subjects that do not have mutations. Affymetrix U133 plus 2 chips were used to profile the transcriptome of BRCA1 or BRCA2 mutant and wild type. In total 36 chips were used to profile 18 samples from both breast and ovary, 6 mutant (BRCA1 and BRCA2) and 6 wild type.