Haplo-insufficiency of BRCA1 in sporadic breast cancer.
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.
Staff
Synnöve
S
Laboratory of Cancer Biology, Institute of Medical Technology, University Hospital of Tampere, Tampere, Finland.
Isola
Jorma
J
Tanner
Minna
M
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
D012333:RNA, Messenger