Title: A Novel Mouse Model for Uterine Leiomyoma PROJECT SUMMARY: Uterine leiomyomas or fibroids (UL) are the most common human tumors and create a huge financial burden for the United States health care system. These tumors affect millions of women worldwide and can cause significant morbidity. Uterine leiomyomas constitute a heterogeneous group of tumors based on histology, genetics and clinical presentation. There are at least 6 major histologically defined types: usual leiomyoma, cellular leiomyoma, mitotically active leiomyoma, atypical leiomyoma, smooth muscle tumor of uncertain malignant potential (STUMP), and leiomyosarcoma. MED12 is a component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II- dependent genes and MED12 is frequently mutated in the usual leiomyomas (>70%) but less common in other histological variants of leiomyomas and leiomyosarcomas. Recent molecular genetic evidence suggests that some of the leiomyosarcomas may evolve from preexisting atypical leiomyomas. Leiomyosarcomas are highly malignant and have a high risk of recurrence with poor prognosis. A mouse model of atypical leiomyoma will be necessary to test the hypothesis that atypical uterine leiomyomas may progress to leiomyosarcoma or even carcinosarcoma. We have generated a uterine leiomyoma mouse model by conditionally activating the MAP Kinase (with activating KRAS mutations) and PI3K-AKT (with PTEN knockout) pathways. Our mouse model appears to be of atypical leiomyoma and with leiomyosarcoma features during tumor progression. To further understand the progression of leiomyoma to leiomyosarcoma, (1) we will investigate whether activation of MAP Kinase and PI3K-AKT pathways are involved in the oncogenesis of atypical leiomyoma. We will perform functional proteomic analysis of human leiomyoma samples by reverse phase protein arrays to detect if the MAP kinase and PI3K-AKT pathways are up-regulated in atypical leiomyomas or not, and we will analyze the KRAS mutation status in atypical leiomyoma using a novel COLD-PCR deep sequencing method; (2) we will also investigate whether TP53 mutation contribute to the progression of leiomyoma to leiomyosarcoma by generating a triple mutant mouse with Ahmr2-Cre Pten(-/-) KrasG12V(+/-)TP53R172H/+ genotype. The knowledge gained and the mouse models developed will help us to better understand the molecular mechanism(s) for uterine smooth muscle oncogenesis in the future. This will also lay the foundation for future more efficient targeted therapy development.
Uterine leiomyoma is commonly called ?fibroid?, which is a benign tumor of the uterine smooth muscle. In United States, fibroids account for 30% of all hysterectomies among women ages 18 to 44 years with an estimated annual health care cost more than $9 billion. The proposed study of the novel fibroid mouse model will provide new insight to target specific mechanisms involved in the development and progression of uterine leiomyoma.