Biology subjects

Lydon, J. P.

Publications and source records attributed to Lydon, J. P..

3 recordsLinked to original sources

bioRxiv2020

Pten and Dicer1 loss causes poorly-differentiated endometrial adenocarcinoma in mice

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. In an endometrial adenocarcinoma mouse model, which has a conditional uterine deletion of Pten, Dicer1 was also conditionally deleted. Conditional uterine deletion of Dicer1 and Pten resulted in high-penetrance, poorly-differentiated endometrial adenocarcinomas. Poorly-differentiated endometrial adenocarcinomas expressed known markers of clear-cell adenocarcinoma, including Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B). Adenocarcinomas were hormone-independent, and treatment with long-term progesterone did not mitigate poorly-differentiated adenocarcinoma, nor did it affect adnexal metastasis. Transcriptomic analyses of uteri or Ishikawa cells with deletion of DICER1 revealed unique transcriptomic profiles and global downregulation of miRNAs. Integration of downregulated miRNAs with upregulated 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). Importantly, these miRNA-target genes, involved in ephrin-receptor and transforming growth factor-beta signaling, represent potential clinical targets for rare, yet deadly, poorly-differentiated endometrial adenocarcinomas in women. This mouse model represents poorly-differentiated endometrial adenocarcinoma and will allow for the discovery of novel mechanisms of hormone-independent endometrial adenocarcinoma from atrophic endometrium. Significance StatementEndometrial cancer is one of the few cancers with an increasing death rate in the United States. The most significant risk factor associated with death is high tumor grade, which occurs most frequently in postmenopausal women, where it develops within an atrophic endometrium. Here, we present a mouse model with conditional deletion of Dicer1, a key enzyme in miRNA genesis, and Pten, a tumor suppressor, that develops poorly-differentiated, steroid hormone-independent, endometrial adenocarcinoma with adnexal metastasis. These high-grade adenocarcinomas develop from an atrophic endometrium and share molecular features with DICER1-mutant human endometrial adenocarcinomas. We anticipate that this preclinical model represents a move toward the discovery of novel mechanisms of hormone-independent development of endometrial adenocarcinoma from atrophic endometrium.

cancer biology↗

bioRxiv2020

Increased FOXL2 Expression Alters Uterine Structures and Functions

Transcription factor FOXL2 exhibits an increase in mRNA levels in eutopic endometrial biopsy in endometriosis patients. While FOXL2 is known of regulating sex differentiation and reproductive function, the impact of elevated FOXL2 expression on uterine physiology remains unknown. To answer this question, we generated mice with over expression of FOXL2 (FOXL2OE) in the female reproductive tract by crossing Foxl2LsL/+ with the Pgrcre model. FOXL2OE uterus showed severe morphological abnormality including abnormal epithelial stratification, blunted adenogenesis, increased endometrial fibrosis and disrupted myometrial morphology. In contrast, increasing FOXL2 levels specifically in uterine epithelium by crossing the Foxl2LsL/+ with the Ltficre mice resulted in the eFOXL2OE mice with uterine epithelial stratification but without defects in endometrial fibrosis and adenogenesis, demonstrating a role of the endometrial stroma in the uterine abnormalities of the FOXL2OE mice. Transcriptomic analysis of 12 weeks old Pgrcre and FOXL2OE uterus at diestrus stage showed a positive correlation of FOXL2OE uterine transcriptome with human endometrium of endometriosis patients. Furthermore, we found FOXL2OE mice were sterile. The infertility was caused in part by a disruption of the hypophyseal ovarian axis resulting in an anovulatory phenotype. The FOXL2OE mice failed to show decidual responses during artificial decidualization in ovariectomized mice which demonstrates the uterine contribution to the infertility phenotype. These data supported that aberrantly increased FOXL2 expressions in the female reproductive tract can disrupt ovarian and uterine functions, particularly, may be involved in the progressions of endometriosis.

developmental biology↗

bioRxiv2019

Constitutive Expression of the Progesterone Receptor Isoforms Promotes Hormone-Dependent Development of Ovarian Neoplasms

Abnormal expression of the progesterone receptor (PGR) isoforms, PGRA and PGRB, is often observed in women with reproductive tract cancer. To assess the importance of the PGR isoform ratio in the maintenance of the healthy reproductive tract, mice with Cre recombinase- activated PGRA and PGRB transgenes were bred with the PGRCre mouse model to generate strains expressing either PGRA or PGRB in PGR positive tissues. The PGRB mice developed ovarian neoplasms at 23 weeks of age derived from ovarian luteal cells, while the PGRA expressing mice displayed a reduced frequency of tumor development. Transcriptomic analyses of the ovarian tumors revealed an enhanced AKT pathway signature, which is in agreement with expression changes found in human ovarian adenocarcinoma. Effective treatment with the PGR antagonist RU486 reduced tumor growth and the expression of cell cycle genes. We concluded that tumor growth and proliferation is hormone and PGR isoform dependent. Further analysis of the PGRB cistrome identified binding events of critical mitotic phase entry genes. This work suggests an intriguing mechanism whereby the expression of the PGR isoforms determines in vivo neoplasia through high-jacking of the cell cycle pathway.

cancer biology↗