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Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo

Oncogene volume 30, pages 3522–3536 (2011)Cite this article

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Abstract

Ovarian cancer is a complex and deadly disease that remains difficult to detect at an early curable stage. Furthermore, although some oncogenic (Kras, Pten/PI3K and Trp53) pathways that are frequently mutated, deleted or amplified in ovarian cancer are known, how these pathways initiate and drive specific morphological phenotypes and tumor outcomes remain unclear. We recently generated Ptenfl/fl; KrasG12D; Amhr2-Cre mice to disrupt the Pten gene and express a stable mutant form of KrasG12D in ovarian surface epithelial (OSE) cells. On the basis of histopathologic criteria, the mutant mice developed low-grade ovarian serous papillary adenocarcinomas at an early age and with 100% penetrance. This highly reproducible phenotype provides the first mouse model in which to study this ovarian cancer subtype. OSE cells isolated from ovaries of mutant mice at 5 and 10 weeks of age exhibit temporal changes in the expression of specific Mullerian epithelial marker genes, grow in soft agar and develop ectopic invasive tumors in recipient mice, indicating that the cells are transformed. Gene profiling identified specific mRNAs and microRNAs differentially expressed in purified OSE cells derived from tumors of the mutant mice compared with wild-type OSE cells. Mapping of transcripts or genes between the mouse OSE mutant data sets, the Kras signature from human cancer cell lines and the human ovarian tumor array data sets, documented significant overlap, indicating that KRAS is a key driver of OSE transformation in this context. Two key hallmarks of the mutant OSE cells in these mice are the elevated expression of the tumor-suppressor Trp53 (p53) and its microRNA target, miR-34a-c. We propose that elevated TRP53 and miR-34a-c may exert negatively regulatory effects that reduce the proliferative potential of OSE cells leading to the low-grade serous adenocarcinoma phenotype.

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Acknowledgements

We Alan J Herron DVM, Professor and Head of the Comparative Pathology Laboratory for his advice and insights into the mouse ovarian tumor phenotype, Yuet Lo and Azam Zariff for technical assistance and the Microscopy Core at Baylor College of Medicine for their expertise. We also thank the Immunohistochemistry Laboratory at The University of Texas MD Anderson Cancer Center for performing the calretinin and ESR1 immunostaining. Supported in part by NIH-HD-16229 (JSR), NRSA (LM), a Program Project Development Grant from the Ovarian Cancer Research Fund (CJC, PG, MA) and The University of Texas MD Anderson Cancer Center Specialized Program of Research Excellence in Ovarian Cancer (P50 CA08369) (KKW).

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    L K Mullany, H-Y Fan, Z Liu, A Marshall, L Xin & J S Richards

  2. Department of Molecular and Human Genetics and Molecular and Cellular Biology and the Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    L D White & C J Creighton

  3. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    P Gunaratne

  4. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    M L Anderson

  5. Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA

    M Deavers

  6. Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, TX, USA

    K-K Wong

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Mullany, L., Fan, HY., Liu, Z. et al. Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo. Oncogene 30, 3522–3536 (2011). https://doi.org/10.1038/onc.2011.70

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