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

Xiyin Wang, Jillian R H Wendel, Robert E Emerson, Russell R Broaddus, Chad J Creighton, Douglas B Rusch, Aaron Buechlein, Francesco J DeMayo, John P Lydon, Shannon M Hawkins

Oncogene 2020 Oct

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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.

Citation

Xiyin Wang, Jillian R H Wendel, Robert E Emerson, Russell R Broaddus, Chad J Creighton, Douglas B Rusch, Aaron Buechlein, Francesco J DeMayo, John P Lydon, Shannon M Hawkins. Pten and Dicer1 loss in the mouse uterus causes poorly differentiated endometrial adenocarcinoma. Oncogene. 2020 Oct;39(40):6286-6299