Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53.
BACKGROUND
Approximately one out of every ten cases of epithelial ovarian cancer (EOC) is inherited. The majority of inherited cases of EOC result from mutations in the breast cancer associated gene 1 (BRCA1). In addition to mutation of BRCA1, mutation of the p53 gene is often found in patients with inherited breast and ovarian cancer syndrome.


RESULTS
We investigated the role of loss of function of BRCA1 and p53 in ovarian cancer development using mouse models with conditionally expressed alleles of Brca1 and/or p53. Our results show that ovary-specific Cre-recombinase-mediated conditional inactivation of both Brca1(LoxP/LoxP) and p53(LoxP/LoxP) resulted in ovarian or reproductive tract tumor formation in 54% of mice, whereas conditional inactivation of either allele alone infrequently resulted in tumors (< or =5% of mice). In mice with conditionally inactivated Brca1(LoxP/LoxP) and p53(LoxP/LoxP), ovarian tumors arose after long latency with the majority exhibiting histological features consistent with high grade leiomyosarcomas lacking expression of epithelial, follicular or lymphocyte markers. In addition, tumors with conditional inactivation of both Brca1(LoxP/LoxP) and p53(LoxP/LoxP) exhibited greater genomic instability compared to an ovarian tumor with inactivation of only p53(LoxP/LoxP).


CONCLUSIONS
Although conditional inactivation of both Brca1 and p53 results in ovarian tumorigenesis, our results suggest that additional genetic alterations or alternative methods for targeting epithelial cells of the ovary or fallopian tube for conditional inactivation of Brca1 and p53 are required for the development of a mouse model of Brca1-associated inherited EOC.
Quinn
Bridget A
BA
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Brake
Tiffany
T
Hua
Xiang
X
Baxter-Jones
Kimberly
K
Litwin
Samuel
S
Ellenson
Lora Hedrick
LH
Connolly
Denise C
DC
D000256:Adenoviridae / Q000235:genetics; D000483:Alleles; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D005260:Female; D020868:Gene Silencing; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007890:Leiomyosarcoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases