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. 2006 Sep 15;66(18):8949-53.
doi: 10.1158/0008-5472.CAN-06-1495.

A mouse model for the molecular characterization of brca1-associated ovarian carcinoma

Deyin Xing  1 , Sandra Orsulic
Affiliations

A mouse model for the molecular characterization of brca1-associated ovarian carcinoma

Deyin Xing et al. Cancer Res. .

Abstract

Little is known about the mechanisms that underlie Brca1-associated ovarian tumorigenesis, mainly due to the lack of an appropriate experimental model. We developed genetically defined primary mouse ovarian surface epithelial (OSE) cell lines in which the loss of functional Brca1 and p53 recapitulates the events that are thought to occur in early ovarian cancer development in patients with Brca1 mutations. This system allows for the introduction of additional oncogenes that are thought to cooperate with the loss of Brca1 and p53 to induce tumorigenesis. We showed that Myc is sufficient to induce transformation of ovarian cells that are deficient for both Brca1 and p53 but not sufficient for the transformation of cells that are deficient for either Brca1 or p53. The transformed Brca1-deficient OSE cells display an increased number of centrosomes, acquire complex chromosome aberrations, and lack Rad51 nuclear foci in the presence of DNA-damaging agents, such as mitomycin C and cisplatin. Immunocompetent mice injected with transformed OSE cells develop tumors that resemble human metastatic serous ovarian carcinoma, the most common type of ovarian cancer in women. Consistent with the reported platinum chemosensitivity in patients with Brca1-associated ovarian cancer, the Brca1-deficient OSE cells have increased sensitivity to the DNA-damaging agent cisplatin, whereas sensitivity to the microtubule poison paclitaxel is similar between Brca1 wild-type and Brca1-deficient cells. The Brca1 wild-type and Brca1-deficient mouse ovarian tumors and cell lines provide a new experimental system for the evaluation of therapies that target the Brca1 pathway.

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Figures

Figure 1
Figure 1
Characterization of genetically defined mouse ovarian cancer cell lines. A, detection of deleted p53 (exons 2–10), conditional Brca1, deleted Brca1 (exon 11), and tva alleles by PCR using DNA from mouse tails (2, 5, 6) and the corresponding transformed ovarian cell lines with deleted p53 and Brca1 tumor suppressor genes (BR2, BR5, and BR6). B, RT-PCR detection of p53, Brca1, Myc, and β-actin in MEFs and engineered mouse ovarian cancer cell lines C1 (p53−/−; Myc; K-ras), C2 (p53−/−; Myc; Akt), C3 (p53−/−; K-ras; Akt), and BR2, BR5, and BR6 (p53−/−; Brca1−/−; Myc). C, Western blot of whole-cell extracts from Brca1 wild-type (C22) and Brca1-deficient (BR2) cell lines with a mouse Brca1 antibody. Asterisk, nonspecific band. D, immunodetection of Rad51 nuclear foci formation after overnight exposure of Brca1 wild-type (C11) and Brca1-deficient (BR5) OSE cell lines to 1μg/mL MMC or vehicle.
Figure 2
Figure 2
Phenotypic properties of transformed ovarian cells and tumors that are wild-type or deficient for Brca1. A, ascites accumulation and carcinomatosis are apparent 4 to 10 weeks after i.p. injection of the Brca1 wild-type C2 cells (n = 10) and 10 to 14 weeks after i.p. injection of the Brca1-deficient BR5 cells (n = 16) into FVB mice. B, Brca1 wild-type and Brca1-deficient mouse tumors resemble human ovarian serous papillary carcinoma. H&E staining. C, Brca1 wild-type and Brca1-deficient mouse tumors are positive for the epithelial marker keratin 8 (K8).
Figure 3
Figure 3
Sensitivity of Brca1 wild-type and Brca1-deficient cells to drugs with differential mechanisms of action. A, sensitivity of Brca1 wild-type (C1, C2, C3, T1, T2, and T3) and Brca1-deficient (BR2, BR5, BR6, TBR2, TBR5, and TBR6) cell lines to the microtubule poison paclitaxel and the DNA-damaging agent cisplatin. Results are ratio of the number of drug-treated cells to that of control cells. Points, mean of triplicate experiments; bars, SD. B, metaphase chromosome analysis of Brca1 wild-type (T1) and Brca1-deficient (TBR5) cell lines left untreated (inset) or exposed to 1 μmol/L cisplatin for 48 hours (main). Asterisks, triradial or quadriradial chromosomes.
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References

    1. Cass I, Baldwin RL, Varkey T, et al. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 2003;97:2187–95. - PubMed
    1. Werness BA, Parvatiyar P, Ramus SJ, et al. Ovarian carcinoma in situ with germline BRCA1 mutation and loss of heterozygosity at BRCA1 and TP53. J Natl Cancer Inst. 2000;92:1088–91. - PubMed
    1. Ramus SJ, Bobrow LG, Pharoah PD, et al. Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer. 1999;25:91–6. - PubMed
    1. Schuyer M, Berns EM. Is TP53 dysfunction required for BRCA1-associated carcinogenesis? Mol Cell Endocrinol. 1999;155:143–52. - PubMed
    1. Orsulic S, Li Y, Soslow RA, et al. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell. 2002;1:53–62. - PMC - PubMed

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