Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes.
Epithelial ovarian cancer (EOC) is thought to arise 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. Using mice with conditional expression of Brca1, we inactivated Brca1 in the murine OSE and demonstrate that this inactivation results in the development of preneoplastic changes, such as hyperplasia, epithelial invaginations, and inclusion cysts, which arise earlier and are more numerous than in control ovaries. These changes resemble the premalignant lesions that have been reported in human prophylactic oophorectomy specimens from women with BRCA1 germline mutation. We also report that inactivation of Brca1 in primary cultures of murine OSE cells leads to a suppression of proliferation due to increased apoptosis that can be rescued by concomitant inactivation of p53. These observations, along with our finding that these cells display an increased sensitivity to the DNA-damaging agent cisplatin, indicate that loss of function of Brca1 in OSE cells impacts both cellular growth control and DNA-damage repair which results in altered cell behavior manifested as morphological changes in vivo that arise earlier and are more numerous than what can be attributed to ageing.
Clark-Knowles
Katherine V
KV
Department of Cellular and Molecular Medicine, University of Ottawa, 501 Smyth Rd., Box 926, Ottawa, Ontario, Canada K1H 8L6. kclar075@uottawa.ca
Garson
Kenneth
K
Jonkers
Jos
J
Vanderhyden
Barbara C
BC
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D018390:Gene Targeting; D019398:Genes, BRCA1; D016158:Genes, p53; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D002945:Cisplatin