Browsing by Author "Lydon, John P."

Now showing 1 - 4 of 4
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    CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
    (Springer Nature, 2023-06-03) Yang, Seung Chel; Park, Mira; Hong, Kwon-Ho; La, Hyeonwoo; Park, Chanhyeok; Wang, Peike; Li, Gaizhen; Chen, Qionghua; Choi, Youngsok; DeMayo, Francesco J.; Lydon, John P.; Skalnik, David G.; Lim, Hyunjung J.; Hong, Seok-Ho; Park, So Hee; Kim, Yeon Sun; Kim, Hye-Ryun; Song, Haengseok; Biology, School of Science
    Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4 response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1d/d ectopic lesions showed P4 resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P4 targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.
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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.
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    Vaginal Squamous Cell Carcinoma Develops in Mice with Conditional Arid1a Loss and Gain of Oncogenic Kras Driven by Progesterone Receptor Cre
    (Elsevier, 2021) Wang, Xiyin; Praça, Mariana S.L.; Wendel, Jillian R.H.; Emerson, Robert E.; DeMayo, Francesco J.; Lydon, John P.; Hawkins, Shannon M.; Obstetrics and Gynecology, School of Medicine
    Oncogenic KRAS mutations are a common finding in endometrial cancers. Recent sequencing studies indicate that loss-of-function mutations in the ARID1A gene are enriched in gynecologic malignant tumors. However, neither of these genetic insults alone are sufficient to develop gynecologic cancer. To determine the role of the combined effects of deletion of Arid1a and oncogenic Kras, Arid1aflox/flox mice were crossed with KrasLox-Stop-Lox-G12D/+ mice using progesterone receptor Cre (PgrCre/+). Histologic analysis and immunohistochemistry of survival studies were used to characterize the mutant mouse phenotype. Hormone dependence was evaluated by ovarian hormone depletion and estradiol replacement. Arid1aflox/flox; KrasLox-Stop-Lox-G12D/+; PgrCre/+ mice were euthanized early because of invasive vaginal squamous cell carcinoma. Younger mice had precancerous intraepithelial lesions. Immunohistochemistry supported the pathological diagnosis with abnormal expression and localization of cytokeratin 5, tumor protein P63, cyclin-dependent kinase inhibitor 2A, and Ki-67, the marker of proliferation. Ovarian hormone deletion in Arid1aflox/flox; KrasLox-Stop-Lox-G12D/+; PgrCre/+ mice resulted in atrophic vaginal epithelium without evidence of vaginal tumors. Estradiol replacement in ovarian hormone-depleted Arid1aflox/flox; KrasLox-Stop-Lox-G12D/+; PgrCre/+ mice resulted in lesions that resembled the squamous cell carcinoma in intact mice. Therefore, this mouse can be used to study the transition from benign precursor lesions into invasive vaginal human papillomavirus-independent squamous cell carcinoma, offering insights into progression and pathogenesis of this rare disease.