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Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis

Oncogene volume 31, pages 1504–1520 (2012)Cite this article

Abstract

WNT, RAS or phosphoinositide 3-kinase signaling pathways control specific stages of ovarian follicular development. To analyze the functional interactions of these pathways in granulosa cells during follicular development in vivo, we generated specific mutant mouse models. Stable activation of the WNT signaling effector β-catenin (CTNNB1) in granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life or following targeted deletion of the tumor suppressor gene Pten. Conversely, expression of oncogenic KRASG12D dramatically arrests proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine whether KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1-mutant mice. Unexpectedly, transgenic Ctnnb1;Kras-mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation and developed early-onset GCTs leading to premature death in a manner similar to the Ctnnb1;Pten-mutant mice. Microarray and reverse transcription–PCR analyses revealed that gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. The concomitant activation of CTNNB1 and KRAS in Sertoli cells also caused testicular granulosa cell tumors that showed gene expression patterns that partially overlapped those observed in GCTs of the ovary. Although the mutations analyzed herein have not yet been linked to adult GCTs in humans, they may be related to juvenile GCTs or to tumors in other tissues where CTNNB1 is mutated. Importantly, the results provide strong evidence that CTNNB1 is the driver in these contexts and that KRASG12D and Pten loss promote the program set in motion by the CTNNB1.

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Acknowledgements

We thank the Microarray Core Facility at Baylor College of Medicine (Lisa K White, director) for performing the microarray analyses. Supported, in part, by NIH-HD-16229 and the Eunice Kennedy Shriver NICHD/NIH cooperative agreement (U54-(HD07945)) as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (JSR), an operating grant from the Canadian Institutes of Health Research (DB) and a Discovery Grant from the National Sciences and Engineering Research Council (DB). We also acknowledge that hormone assays were done by The University of Virginia Research in Reproduction Ligand Assay and Analysis Core supported by the Eunice Kennedy Shriver NICHD/NIH (SCCPIR) grant U54-HD29034.

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

    J S Richards, H-Y Fan & Z Liu

  2. Department de biomedicine Veterinaire, Centre de Recherche en Reproduction Animale, Université de Montreal, Saint-Hyacinthe, Québec, Canada

    M Tsoi, M-N Laguë, A Boyer & D Boerboom

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Richards, J., Fan, HY., Liu, Z. et al. Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis. Oncogene 31, 1504–1520 (2012). https://doi.org/10.1038/onc.2011.341

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