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Cell Type–Specific Targeted Mutations of Kras and Pten Document Proliferation Arrest in Granulosa Cells versus Oncogenic Insult to Ovarian Surface Epithelial Cells

¹ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas and ² Comparative Medicine and Animal Resources Center, McGill University, Montreal, Quebec, Canada

Requests for reprints: JoAnne S. Richards, Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Phone: 713-798-6259; Fax: 713-790-1275; E-mail: joanner{at}bcm.edu.

Key Words: ovary • granulosa cell • Kras • Pten • oncogenes • ovarian cancer • follicle development

The small G-protein KRAS is crucial for mediating gonadotropin-induced events associated with ovulation. However, constitutive expression of Kras^G12D in granulosa cells disrupted normal follicle development leading to the persistence of abnormal follicle-like structures containing nonmitotic cells. To determine what factors mediate this potent effect of Kras^G12D, gene profiling analyses were done. We also analyzed Kras^G12D;Cyp19-Cre and Kras^G12;Pgr-Cre mutant mouse models that express Cre prior to or after the initiation of granulosa cell differentiation, respectively. Kras^G12D induced cell cycle arrest in granulosa cells of the Kras^G12D;Cyp19-Cre mice but not in the Kras^G12D;Pgr-Cre mice, documenting the cell context–specific effect of Kras^G12D. Expression of Kras^G12D silenced the Kras gene, reduced cell cycle activator genes, and impaired the expression of granulosa cell and oocyte-specific genes. Conversely, levels of PTEN and phosphorylated p38 mitogen-activated protein kinase (MAPK) increased markedly in the mutant granulosa cells. Because disrupting Pten in granulosa cells leads to increased proliferation and survival, Pten was disrupted in the Kras^G12D mutant mice. The Pten/Kras mutant mice were infertile but lacked granulosa cell tumors. By contrast, the Pten^fl/fl;Kras^G12D;Amhr2-Cre mice developed aggressive ovarian surface epithelial cell tumors that did not occur in the Pten^fl/fl;Kras^G12D;Cyp19-Cre or Pten^fl/fl;Kras^G12D;Pgr-Cre mouse strains. These data document unequivocally that Amhr2-Cre is expressed in and mediates allelic recombination of oncogenic genes in ovarian surface epithelial cells. That Kras^G12D/Pten mutant granulosa cells do not transform but rather undergo cell cycle arrest indicates that they resist the oncogenic insults of Kras/Pten by robust self-protecting mechanisms that silence the Kras gene and elevate PTEN and phosphorylated p38 MAPK. [Cancer Res 2009;69(16):6463–72]

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