miRNA and Cox-2 regulation in uterine biology and cancer.

It is estimated that there are more than 1,000 microRNAs (miRNAs) in the human genome, responsible for regulating 30 percent of protein-coding pathways. miRNAs regulate cell growth and differentiation, and have been implicated as causal agents in major diseases such as cancer. In 2007, our lab published the first paper examining the role of miRNAs in the uterus. Using experiments in pregnant mice and HeLa cells derived from human cervical carcinoma, we demonstrated the presence of two miRNAs regulating Cox-2 in the uterus during implantation. These experiments have provided a springboard for expanded study of the roles miRNAs play in both pregnancy events and female reproductive cancers.

PTEN and uterine carcinoma: conditionally gene-deleted mouse models.

Endometrial cancer (EMC) affects 40,000 US women per year, leading to 7,000 deaths. Its etiology is not fully understood. Genetic mutations affecting the phosphatase and tensin homologue (PTEN) gene are observed in the majority of EMC type I cases, while genetic mutations of p53 are found in the majority of EMC type II cases. Mouse models are invaluable in studying the development and progression of the disease, but until recently models were imprecise. Homozygous mutation of PTENin mice results in embryonic lethality, though 20 percent of heterozygous models expressed EMC by 10 months. p53 mutant mice develop many types of cancer, making it difficult to specifically study EMC. In 2008, Takiko Daikoku, in our division, created mouse models with conditional deletion of endometrial PTEN, conditional deletion of endometrial p53, and combined deletion of both genes. Those mouse models present pervasive EMC at a young age, without the presentation of other cancers. This has allowed for more targeted studies of the factors leading to EMC development and progression.