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Pten and Dicer1 loss in the mouse uterus causes poorly differentiated endometrial adenocarcinoma

Oncogene volume 39, pages 6286–6299 (2020)Cite this article

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Abstract

Endometrial cancer remains the most common gynecological malignancy in the United States. While the loss of the tumor suppressor, PTEN (phosphatase and tensin homolog), is well studied in endometrial cancer, recent studies suggest that DICER1, the endoribonuclease responsible for miRNA genesis, also plays a significant role in endometrial adenocarcinoma. Conditional uterine deletion of Dicer1 and Pten in mice resulted in poorly differentiated endometrial adenocarcinomas, which expressed Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B), markers of clear-cell adenocarcinoma. Adenocarcinomas were hormone-independent. Treatment with progesterone did not mitigate poorly differentiated adenocarcinoma, nor did it affect adnexal metastasis. Transcriptomic analyses of DICER1 deleted uteri or Ishikawa cells revealed unique transcriptomic profiles and global miRNA downregulation. Computational integration of miRNA with mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published human DICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas). Similar to human endometrial cancers, tumors exhibited dysregulation of ephrin-receptor signaling and transforming growth factor-beta signaling pathways. LIM kinase 2 (LIMK2), an essential molecule in p21 signal transduction, was significantly upregulated and represents a novel mechanism for hormone-independent pathogenesis of endometrial adenocarcinoma. This preclinical mouse model represents the first genetically engineered mouse model of poorly differentiated endometrial adenocarcinoma.

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Fig. 1: Unique morphology and poor survival with deletion of Dicer1.
Fig. 2: Invasive adenocarcinoma with metastasis to the adnexa.
Fig. 3: Poorly differentiated adenocarcinomas from 12-week-old dcKO mice expressed clear-cell adenocarcinoma markers.
Fig. 4: Unique cellular characteristics and transcriptomic profile with loss of two alleles of DICER1.
Fig. 5: Dysregulation of ephrin-receptor signaling genes with DICER1 deletion.
Fig. 6: Downregulated miRNAs and upregulated TGFβ signaling genes.

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Acknowledgements

We acknowledge the Indiana Center for Musculoskeletal Health Histology Core at Indiana University School of Medicine and the Human Tissue and Acquisition and Pathology Core at the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine for histology services; the Center for Genomics and Bioinformatics for RNA sequencing, and the Center for Medical Genomics for RNA quality control analysis. We appreciate Dr. Ken Nephew for thoughtful review and comments. These studies were supported by the Indiana Clinical Translational Sciences Institute funded, in part, by Award Number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. These studies were supported by a Uterine SPORE Career Development Award from MD Anderson Cancer Center P50-CA098258 (to SMH) and the Intramural Research Program of the National Institute of Environmental Health Sciences supported FJD: Project Z1AES103311-01.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA

    Xiyin Wang, Jillian R. H. Wendel & Shannon M. Hawkins

  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Robert E. Emerson

  3. Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Russell R. Broaddus

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

    Chad J. Creighton

  5. Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, USA

    Douglas B. Rusch & Aaron Buechlein

  6. National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA

    Francesco J. DeMayo

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

    John P. Lydon

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Wang, X., Wendel, J.R.H., Emerson, R.E. et al. Pten and Dicer1 loss in the mouse uterus causes poorly differentiated endometrial adenocarcinoma. Oncogene 39, 6286–6299 (2020). https://doi.org/10.1038/s41388-020-01434-5

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