Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53.
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-12-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2796165?pdf=render |
| _version_ | 1811259397097127936 |
|---|---|
| author | Bridget A Quinn Tiffany Brake Xiang Hua Kimberly Baxter-Jones Samuel Litwin Lora Hedrick Ellenson Denise C Connolly |
| author_facet | Bridget A Quinn Tiffany Brake Xiang Hua Kimberly Baxter-Jones Samuel Litwin Lora Hedrick Ellenson Denise C Connolly |
| author_sort | Bridget A Quinn |
| collection | DOAJ |
| description | 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.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).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. |
| first_indexed | 2024-04-12T18:30:46Z |
| format | Article |
| id | doaj.art-291e5f9d272846efa14d0605efad0cc7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T18:30:46Z |
| publishDate | 2009-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-291e5f9d272846efa14d0605efad0cc72022-12-22T03:21:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-12-01412e840410.1371/journal.pone.0008404Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53.Bridget A QuinnTiffany BrakeXiang HuaKimberly Baxter-JonesSamuel LitwinLora Hedrick EllensonDenise C ConnollyApproximately 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.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).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.http://europepmc.org/articles/PMC2796165?pdf=render |
| spellingShingle | Bridget A Quinn Tiffany Brake Xiang Hua Kimberly Baxter-Jones Samuel Litwin Lora Hedrick Ellenson Denise C Connolly Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53. PLoS ONE |
| title | Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53. |
| title_full | Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53. |
| title_fullStr | Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53. |
| title_full_unstemmed | Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53. |
| title_short | Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53. |
| title_sort | induction of ovarian leiomyosarcomas in mice by conditional inactivation of brca1 and p53 |
| url | http://europepmc.org/articles/PMC2796165?pdf=render |
| work_keys_str_mv | AT bridgetaquinn inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 AT tiffanybrake inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 AT xianghua inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 AT kimberlybaxterjones inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 AT samuellitwin inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 AT lorahedrickellenson inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 AT denisecconnolly inductionofovarianleiomyosarcomasinmicebyconditionalinactivationofbrca1andp53 |