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Mutant BRCA1 genes antagonize phenotype of wild-type BRCA1
1Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, NY 11040, USA.
Abstract:
Unregulated expression of wild-type BRCA1 (wtBRCA1) confers an altered phenotype in cultured human prostate cancer cells, characterized by chemosensitivity, susceptibility to apoptosis, decreased DNA repair activity, and alterations of key cell regulatory proteins. We now report that the expression of truncated or mutant full-length BRCA1 genes can abrogate certain phenotypic characteristics and/or confer the opposite phenotype to the wild-type BRCA1 gene. In particular, several carboxyl-terminal truncated BRCA1 proteins conferred chemoresistance, decreased susceptibility to apoptosis, and decreased ability to suppress in vivo tumor growth. These truncated BRCA1 proteins also blocked the ability of ectopically expressed wtBRCA1 to induce chemosensitivity and to inhibit estrogen receptor transcriptional activity. Studies using epitope-tagged truncated proteins confirmed their expression, nuclear localization, and functionality. On the other hand, in cells with no endogenous wild-type BRCA1 (HCC1937 human breast cancer cells), the wtBRCA1 gene enhanced cellular DNA repair activity and rendered the cells resistant to DNA damage; while truncated BRCA1 proteins blocked the wtBRCA1-induced chemoresistance. Our findings suggest that truncated BRCA1 proteins can inhibit the function of wild-type BRCA1. They raise the possibility that some inherited BRCA1 mutations may actively promote oncogenesis by blocking the function of the remaining wild-type BRCA1 allele, although this hypothesis remains to be proved.
Insights
Truncated BRCA1 proteins can block wild-type BRCA1 function, leading to chemoresistance and reduced apoptosis in cancer cells. This suggests some inherited BRCA1 mutations may promote cancer by inhibiting normal BRCA1 activity.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Cellular Biology
Background:
- Wild-type BRCA1 (wtBRCA1) regulates cell phenotype, including chemosensitivity and DNA repair.
- Altered BRCA1 expression is implicated in various cancers, particularly breast and prostate cancer.
Purpose of the Study:
- To investigate the functional impact of truncated or mutant BRCA1 proteins on cellular phenotypes.
- To determine if truncated BRCA1 can antagonize the tumor-suppressive functions of wtBRCA1.
Main Methods:
- Expression of wild-type, truncated, and mutant BRCA1 genes in human prostate cancer cell lines.
- Assessment of cellular phenotypes including chemosensitivity, apoptosis susceptibility, and DNA repair activity.
- Studies in HCC1937 breast cancer cells lacking endogenous BRCA1.
Main Results:
- Carboxyl-terminal truncated BRCA1 proteins conferred chemoresistance, decreased apoptosis susceptibility, and reduced tumor growth suppression.
- Truncated BRCA1 proteins inhibited the ability of wtBRCA1 to induce chemosensitivity and suppress estrogen receptor activity.
- In BRCA1-deficient cells, truncated BRCA1 proteins blocked wtBRCA1-mediated chemoresistance and enhanced DNA repair.
Conclusions:
- Truncated BRCA1 proteins can inhibit the tumor-suppressive functions of wild-type BRCA1.
- Inherited BRCA1 mutations producing truncated proteins might actively promote oncogenesis by blocking wtBRCA1 function.