Browsing by Author "DeMayo, Francesco J."

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    Pten and Dicer1 loss in the mouse uterus causes poorly-differentiated endometrial adenocarcinoma
    (Springer Nature, 2020-10) Wang, Xiyin; Wendel, Jillian R. H.; Emerson, Robert E.; Broaddus, Russell R.; Creighton, Chad J.; Rusch, Douglas B.; Buechlein, Aaron; DeMayo, Francesco J.; Lydon, John P.; Hawkins, Shannon M.; Obstetrics and Gynecology, School of Medicine
    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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    Targeting progesterone signaling prevents metastatic ovarian cancer
    (National Academy of Science, 2020-12-15) Kim, Olga; Park, Eun Young; Kwon, Sun Young; Shin, Sojin; Emerson, Robert E.; Shin, Yong-Hyun; DeMayo, Francesco J.; Lydon, John P.; Coffey, Donna M.; Hawkins, Shannon M.; Quilliam, Lawrence A.; Cheon, Dong-Joo; Fernández, Facundo M.; Nephew, Kenneth P.; Karpf, Adam R.; Widschwendter, Martin; Sood, Anil K.; Bast, Robert C., Jr.; Godwin, Andrew K.; Miller, Kathy D.; Cho, Chi-Heum; Kim, Jaeyeon; Biochemistry and Molecular Biology, School of Medicine
    Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.