A mouse model for the molecular characterization of brca1-associated ovarian carcinoma.
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.
Xing
Deyin
D
Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Orsulic
Sandra
S
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D019398:Genes, BRCA1; D016259:Genes, myc; D016158:Genes, p53; D051379:Mice; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D019313:BRCA1 Protein; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D002945:Cisplatin