Abstract:
: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.
journal_name
Exp Cell Resjournal_title
Experimental cell researchauthors
Clark-Knowles KV,Garson K,Jonkers J,Vanderhyden BCdoi
10.1016/j.yexcr.2006.09.026subject
Has Abstractpub_date
2007-01-01 00:00:00pages
133-45issue
1eissn
0014-4827issn
1090-2422pii
S0014-4827(06)00416-2journal_volume
313pub_type
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