Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer

Abstract

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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Intrabursal AdCre administration results in efficient infection of the OSE.
Figure 2: Induction of ovarian endometriotic-like lesions and peritoneal endometriosis by oncogenic K-rasG12D.
Figure 3: Characterization of endometriotic lesions.
Figure 4: Combined K-rasG12D activation and conditional deletion of Pten lead to endometrioid ovarian cancer.
Figure 5: Lesion profiles in AdCre-infected LSL-K-rasG12D/+PtenLoxP/loxP and PtenloxP/loxP mice.

References

  1. Ozols, R.F. et al. Focus on epithelial ovarian cancer. Cancer Cell 5, 19–24 (2004).

    CAS  Article  Google Scholar 

  2. Obata, K. et al. Frequent PTEN/MMAC1 mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res. 58, 2095–2097 (1998).

    CAS  PubMed  Google Scholar 

  3. Sato, N. et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 60, 7052–7056 (2000).

    CAS  PubMed  Google Scholar 

  4. Cuatrecasas, M. et al. K-ras mutations in nonmucinous ovarian epithelial tumors. Cancer 82, 1088–1095 (1998).

    CAS  Article  Google Scholar 

  5. Gemignani, M.L. et al. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol. Oncol. 90, 378–381 (2003).

    CAS  Article  Google Scholar 

  6. Hogdall, E.V. et al. K-ras alterations in Danish ovarian tumor patients. From the Danish “Malova” Ovarian cancer study. Gynecol. Oncol. 89, 31–36 (2003).

    CAS  Article  Google Scholar 

  7. Okuda, T. & Okai, T. p53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer. Gynecol. Oncol. 88, 318–325 (2003).

    CAS  Article  Google Scholar 

  8. Orsulic, S. et al. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell 1, 53–62 (2002).

    CAS  Article  Google Scholar 

  9. Connolly, D.C. et al. Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res. 63, 1389–1397 (2003).

    CAS  PubMed  Google Scholar 

  10. Flesken-Nikitin, A., Choi, K.C., Eng, J.P., Shmidt, E.N. & Nikitin, A.Y. Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. Cancer Res. 63, 3459–3463 (2003).

    CAS  PubMed  Google Scholar 

  11. Clement, P.B., Seidman, J.D., Russell, P. & Kurman, R.J. in Blaustein's Pathology of the Female Genital Tract 5th edn (ed. Kurman, R.J.) 746–768, 791–905 (Springer, New York, 2002).

    Google Scholar 

  12. Swiersz, L.M. Role of endometriosis in cancer and tumor development. Ann. NY Acad. Sci. 955, 281–292 (2002).

    Article  Google Scholar 

  13. Jackson, E.L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-RAS. Genes Dev. 15, 3243–3248 (2001).

    CAS  Article  Google Scholar 

  14. Tuveson, D.A. et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2003).

    Article  Google Scholar 

  15. Vercellini, P. et al. Analysis of p53 and ras gene mutations in endometriosis. Gynecol. Obstet. Invest. 38, 70–71 (1994).

    CAS  Article  Google Scholar 

  16. Amemiya, S. et al. Malignant transformation of endometriosis and genetic alterations of K-ras and microsatellite instability. Int. J. Gynecol. Obstet. 86, 371–376 (2004).

    CAS  Article  Google Scholar 

  17. Otsuka, J. et al. K-ras mutation may promote carcinogenesis of endometriosis leading to ovarian clear cell carcinoma. Med. Electron Microsc. 37, 188–192 (2004).

    Article  Google Scholar 

  18. Grunwald, V. et al. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res. 62, 6141–6145 (2002).

    CAS  PubMed  Google Scholar 

  19. Sebolt-Leopold, J.S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. 5, 810–816 (1999).

    CAS  Article  Google Scholar 

  20. Arimoto-Ishida, E. et al. Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. Endocrinology 145, 2014–2022 (2004).

    CAS  Article  Google Scholar 

  21. Lesche, R. et al. Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 32, 148–149 (2002).

    CAS  Article  Google Scholar 

  22. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. in Manipulating the Mouse Embryo 2nd edn 185–186 (Cold Spring Harbor Laboratory Press, Plainview, NY, 1994).

    Google Scholar 

Download references

Acknowledgements

We thank C. P. Crum and D. H. Castrillon for additional pathological analysis and comments and advice. We are grateful to A.Y. Nikitin, A. Flesken-Nikitin, T. C. Hamilton, and R. Bao for sharing their technical expertise and advice. In addition, we would like to thank E. Jarmon for technical assistance, H. Wu for the gift of PtenloxP/loxP mice, and D. Kirsch and D. MacPherson for critical reading of the manuscript. This work was supported by grants from the American Cancer Society and the Shoreline Circle of Hope (D.M.D.), the Anna Fuller Fellowship (D.M.D.), the Mouse Models of Human Cancer Consortium of the National Cancer Institute (T.J.), and a KO8 award (CA 92013) from the National Cancer Institute (T.A.I.). T.J. is an Investigator of the Howard Hughes Medical Institute. This paper is dedicated to the memory of a good friend, I. Triculescu, who fought a courageous battle with ovarian cancer.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tyler Jacks.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Histomorphology of control ovaries. (PDF 65 kb)

Supplementary Fig. 2

Gross pathology of endometriotic lesions. (PDF 253 kb)

Supplementary Fig. 3

Histopathology of endometriotic lesions. (PDF 178 kb)

Supplementary Fig. 4

Gross pathology of ovarian malignant tumors. (PDF 37 kb)

Supplementary Fig. 5

Estrogen receptor immunohistochemistry in control ovaries. (PDF 40 kb)

Supplementary Fig. 6

Phospho-AKT and MAPK immunohistochemistry in control ovaries. (PDF 80 kb)

Supplementary Fig. 7

Negative control slides for immunohistochemistry experiments. (PDF 275 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dinulescu, D., Ince, T., Quade, B. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11, 63–70 (2005). https://doi.org/10.1038/nm1173

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1173

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing