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Preferential allelic expression can lead to reduced expression of BRCA1 in sporadic breast cancers
1Samuel Lunenfeld Research Institute, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.
Abstract:
BRCA1 is considered to be a tumor-suppressor gene, yet mutations in this gene are uncommon in sporadic breast tumors. We investigated whether mechanisms other than DNA mutations that affect the coding region might be involved in breast carcinogenesis. Since loss of expression of the BRCA1 gene would lead to lack of protein, we evaluated the level of BRCA1 mRNA in 21 normal epithelial specimens and in 74 breast carcinomas using quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR). All normal breast epithelial samples expressed BRCA1 mRNA. On the other hand, the tumor specimens exhibited approximately 10-fold range of levels of BRCA1, with some specimens expressing barely detectable amounts of BRCA1 mRNA. The distribution in levels was significantly higher in normal breast epithelial cells than in tumor specimens (p = 0.004). Examination of the BRCA1 locus indicated that deletion of the BRCA1 gene may account for low levels of BRCA1 in a number of specimens. In addition, analysis of samples with relatively reduced levels of BRCA1 expression revealed preferential allele-specific expression in a number of cases, suggesting the presence of regulatory mutations. Our data suggest that the BRCA1 gene may be involved in sporadic breast carcinogenesis through a reduction in gene expression.
Insights
Reduced expression of the BRCA1 gene, not just mutations, may drive sporadic breast cancer. This study found lower BRCA1 mRNA levels in tumors than normal tissue, suggesting altered gene expression plays a role.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRCA1 is a known tumor suppressor gene.
- Mutations in BRCA1 are infrequent in sporadic breast tumors.
- Mechanisms beyond coding region mutations may influence breast cancer development.
Purpose of the Study:
- Investigate mechanisms affecting BRCA1 gene expression in sporadic breast cancer.
- Evaluate BRCA1 mRNA levels in normal and tumor breast tissues.
- Determine if reduced BRCA1 expression contributes to breast carcinogenesis.
Main Methods:
- Quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR) was used to measure BRCA1 mRNA levels.
- BRCA1 mRNA was analyzed in 21 normal breast epithelial samples and 74 breast carcinomas.
- BRCA1 locus and allele-specific expression were examined in tumor specimens.
Main Results:
- All normal breast epithelial samples expressed BRCA1 mRNA.
- Breast tumor specimens showed a 10-fold range in BRCA1 mRNA levels, with some barely detectable.
- Significantly lower BRCA1 mRNA levels were observed in tumor specimens compared to normal cells (p = 0.004).
- Gene deletion and allele-specific expression (suggesting regulatory mutations) were identified as potential causes for reduced BRCA1 expression.
Conclusions:
- Reduced BRCA1 gene expression, potentially due to deletions or regulatory mutations, is implicated in sporadic breast carcinogenesis.
- Mechanisms affecting BRCA1 expression levels are important in breast cancer development.
- Loss of BRCA1 function through reduced expression may contribute to tumor formation.