Abstract
Epithelial ovarian cancer (EOC) is thought to arise in part from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas.
Highlights
Epithelial ovarian cancer (EOC) is thought to arise from the ovarian surface epithelium (OSE) [1], recent evidence implicates the fallopian tube as a potential tissue of origin of EOC of the serous histotype [2,3,4,5]
We have previously shown that inactivation of Brca1 alone in the OSE resulted in an increase in the number of preneoplastic changes in the OSE after 240 days, but no tumor formation [36]
Our previous work showed that when Brca1 was inactivated in vivo via intrabursal injection of AdCre, no tumorigenesis occurred when the animals were followed past one year post-injection, despite the development of significantly more premalignant changes in the OSE of these ovaries [36]
Summary
Epithelial ovarian cancer (EOC) is thought to arise from the ovarian surface epithelium (OSE) [1], recent evidence implicates the fallopian tube as a potential tissue of origin of EOC of the serous histotype [2,3,4,5]. With age and repeated ovulatory cycles, the OSE assumes a more irregular contour and forms invaginations or clefts into the stroma, which may pinch off completely and form epithelial inclusion cysts within the ovary. These crypts and cysts often show evidence of early metaplastic changes in cell shape and express markers up-regulated in ovarian tumors, such as E-cadherin [7] and CA125 [1], which suggests that these premalignant lesions may give rise to ovarian neoplasias. 6% of prophylactically removed ovaries from BRCA1 mutation carriers were found to harbor microscopic ovarian carcinomas [11]
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