title: Haplo-insufficiency of BRCA1 in sporadic breast cancer.
abstract: Copy number deletions and loss of heterozygosity of the BRCA1 gene have been frequently reported in sporadic breast cancer. We studied their relationship with BRCA1 gene expression (the haplo-insufficiency hypothesis) with real-time quantitative reverse transcription-PCR. Expression levels of both full-length and BRCA1-Delta 11b splice variant mRNA were studied, and they showed strong correlation (Pearson r = 0.89). Copy number deletion of BRCA1, found in 45% (27 of 60) of the sporadic breast tumors, was associated with ErbB2 oncogene amplification (P = 0.001) and DNA aneuploidy (P = 0.037), but not with stage, grade, or hormone receptor status. The presence of BRCA1 copy number deletion associated significantly with low levels of full-length BRCA1 mRNA (P < 0.0001). The BRCA1 promoter hypermethylation, found in 6 of 53 tumors (11%) by methylation-specific PCR, was also correlated with low BRCA1 expression (P = 0.005). In statistical multiple regression analysis, decreased expression of BRCA1 mRNA showed strongest association with BRCA1 copy number deletion (P < 0.0001) but was also significantly linked to negative progesterone receptor status (P = 0.02) and BRCA1 promoter hypermethylation (P = 0.041). These findings demonstrate that deletion of the BRCA1 gene copies results in haplo-insufficiency, i.e., decreased BRCA1 mRNA expression. This, in turn, suggests that the BRCA1 gene might have a tumor suppressor function also in sporadic breast cancer.
authors.affiliation: Laboratory of Cancer Biology, Institute of Medical Technology, University Hospital of Tampere, Tampere, Finland.
authors.forename: Synnöve
authors.initials: S
authors.lastname: Staff
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Minna
authors.initials: M
authors.lastname: Tanner
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D019398:Genes, BRCA1 / Q000502:physiology; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger