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Molecular and Cellular Biology, September 2006, p. 6983-6992, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00796-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hyperplasia and Spontaneous Tumor Development in the Gynecologic System in Mice Lacking the BRCA1-11 Isoform

Sang Soo Kim,^1,3 Liu Cao,¹ Sung-Chul Lim,² Cuiling Li,¹ Rui-Hong Wang,¹ Xiaoling Xu,¹ Richard Bachelier,¹ and Chu-Xia Deng^1*

Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10/9N105, 10 Center Drive, Bethesda, Maryland 20892,¹ Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759,² Division of Radiation and Nuclear Medicine, National Cancer Center, Goyang, Gyeonggi 411-769, South Korea³

Received 5 May 2006/ Returned for modification 18 June 2006/ Accepted 30 June 2006

Alternative splicing in the BRCA1 locus generates multiple protein products including BRCA1-11, 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 BRCA1-11, 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 G₁ 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 G₁/S transition, centrosome duplication, and repressing tumor formation.

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* Corresponding author. Mailing address: 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. Phone: (301) 402-7225. Fax: (301) 480-1135. E-mail: ChuxiaD{at}bdg10.niddk.nih.gov.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, September 2006, p. 6983-6992, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00796-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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