Hyperplasia and spontaneous tumor development in the gynecologic system in mice lacking the BRCA1-Delta11 isoform.
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.
Kim
Sang Soo
SS
Genetics 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.
Cao
Liu
L
Lim
Sung-Chul
SC
Li
Cuiling
C
Wang
Rui-Hong
RH
Xu
Xiaoling
X
Bachelier
Richard
R
Deng
Chu-Xia
CX
D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D019313:BRCA1 Protein / Q000172:deficiency*; D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D016193:G1 Phase / Q000528:radiation effects; D005720:Gamma Rays; D017353:Gene Deletion; D018390:Gene Targeting; D005833:Genital Neoplasms, Female / Q000473:pathology*; D005836:Genitalia, Female / Q000166:cytology / Q000473:pathology*; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000166:cytology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D020033:Protein Isoforms / Q000172:deficiency; D016196:S Phase / Q000528:radiation effects
D019313:BRCA1 Protein; C103780:BRCA1-delta11b; D019927:Cyclin E; D020033:Protein Isoforms