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Hyperplasia and spontaneous tumor development in the gynecologic system in mice lacking the BRCA1-Delta11 isoform
Sang Soo Kim1, Liu Cao, Sung-Chul Lim
1Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10/9N105, 10 Center Drive, Bethesda, MD 20892, USA.
Abstract:
Alternative splicing in the BRCA1 locus generates multiple protein products including BRCA1-Delta11, which is identical to the BRCA1 full-length isoform (BRCA1-FL) except for the absence of exon 11. Mutation analysis using gene targeting to create null mutations or disrupt BRCA-FL has provided much of our understanding of BRCA1 functions; however, targeted mutation of specific short forms of BRCA1 has not been reported. To understand the physiologic functions of BRCA1-Delta11, we used a knock-in approach that blocks alternative splicing between exons 10 and 12 to prevent the formation of this form of BRCA1. We showed that homozygous mutant mice (Brca1(FL/FL)) were born at a Mendelian ratio without obvious developmental defects. However, the majority of Brca1(FL/FL) female mice showed mammary gland abnormalities and uterine hyperplasia after one year of age with spontaneous tumor formation. Cultured Brca1(FL/FL) cells exhibited abnormal centrosome amplification and reduction of G(1) population that was accompanied by accumulation of cyclin E and cyclin A. Accumulation of cyclin E was also found in epithelial layers of dilated ducts and hyperproliferative lobular regions in the mammary glands of Brca1(FL/FL) mice. These observations provide evidence that BRCA1 splicing variants are involved in BRCA1 functions in modulating G(1)/S transition, centrosome duplication, and repressing tumor formation.
Insights
Blocking the BRCA1-Delta11 splicing variant in mice prevented its formation, revealing its role in preventing mammary and uterine tumors by regulating cell cycle and centrosome duplication.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Alternative splicing of the BRCA1 gene produces various protein isoforms, including BRCA1-FL and BRCA1-Delta11.
- Understanding the specific roles of these isoforms, particularly BRCA1-Delta11, is crucial for comprehending BRCA1's tumor-suppressive functions.
Purpose of the Study:
- To investigate the physiological functions of the BRCA1-Delta11 splicing variant.
- To determine the impact of selectively blocking BRCA1-Delta11 formation on BRCA1-related cellular processes and tumor development.
Main Methods:
- Utilized a knock-in mouse model engineered to prevent alternative splicing, specifically blocking the formation of BRCA1-Delta11.
- Analyzed Brca1(FL/FL) mice for developmental defects, mammary gland and uterine abnormalities, and tumor formation.
- Examined cultured Brca1(FL/FL) cells for defects in cell cycle progression (G1/S transition) and centrosome duplication.
Main Results:
- Homozygous Brca1(FL/FL) mice were viable and showed no major developmental issues.
- Female Brca1(FL/FL) mice developed mammary gland abnormalities, uterine hyperplasia, and spontaneous tumors by one year of age.
- Brca1(FL/FL) cells displayed centrosome amplification and a reduced G1 population, linked to cyclin E and A accumulation, which was also observed in affected mammary tissues.
Conclusions:
- BRCA1 splicing variants, specifically the absence of BRCA1-Delta11, contribute to BRCA1's functions in cell cycle regulation (G1/S transition) and centrosome duplication.
- The BRCA1-Delta11 isoform plays a significant role in repressing tumor formation, particularly in the mammary and uterine tissues.
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