Nature Medicine11, 63 - 70 (2004)
Published online: 26 December 2004; | doi:10.1038/nm1173
Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer
Daniela M Dinulescu1, 2, Tan A Ince3, 4, 5, Bradley J Quade4, 5, Sarah A Shafer1, 2, Denise Crowley1, 2
& Tyler Jacks1, 2
1
Center for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street, Cambridge, Massachusetts 02139, USA.
2
Department of Biology, Massachusetts Institute of Technology, 40 Ames Street, Cambridge, Massachusetts 02139, USA.
3
Whitehead Institute, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
4
Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
5
These authors contributed equally to this work.
Correspondence should be addressed to Tyler Jacks tjacks@mit.edu
Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.
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