[Frontiers in Bioscience E2, 882-905, June 1, 2010]

Mouse models of uterine corpus tumors: clinical significance and utility

Anne M. Friel1,3, Whitfield B. Growdon1,2,3, Christopher K. McCann1,2,3, Alexander B. Olawaiye1,2,3, Elizabeth G. Munro1,2,3, John O. Schorge2,3, Diego H. Castrillon4, Russell R. Broaddus5, Bo R. Rueda1,2,3,

1Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts 02114, USA, 2Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts 02114, USA, 3Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02114, USA, 4Department of Pathology and Simmons Comprehensive Cancer Center, University Of Texas Southwestern Medical Center, Dallas, TX, 75390, USA, 5Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Endometrial Hyperplasia
3.1. Models presenting with hyperplasia
3.1.1. Steroid hormone models
3.1.1.1. Progesterone receptor knock-out (KO) (PRKO and PRAKO)
3.1.2. Targeted oncogene models
3.1.2.1. Pituitary tumor transforming gene (PTTG)
3.1.3. Epidermal growth factor receptor models
3.1.3.1. EGFR
3.1.3.2. MIG-6
3.1.4. Genetic alterations associated with endometrial hyperplasia
3.1.4.1. BRCA
3.1.4.2. Beta-catenin
3.1.5. Aberrations in matricellular proteins, phosphoproteins and hyperplasia
3.1.5.1. Thrombospondin-1/Integrin beta6
3.1.5.2. Disabled-2
3.1.5.3. HMGA2
4. Endometrial Cancer
4.1. Models presenting with endometrial cancer
4.1.1. Genetic alterations associated with endometrial cancers
4.1.1.1. PTEN and Type I endometrial carcinoma
4.1.2. pten models
4.1.2.1. Non tissue specific deletions
4.1.2.2. Pten+/-/ Mlh1-/- Model
4.1.2.3. Targeted endometrial Pten deletion
4.1.2.4. Pten loss and steroid response
4.1.3. Kinases, kinase interacting proteins, inhibitors and endometrial cancers
4.1.3.1. Cables 1: cyclin-dependent kinase (cdk)-interacting protein
4.1.3.2. LKB1: serine/threonine kinase
4.1.3.3. Par4: kinase inhibition
4.1.4. Replicative aging and endometrial abnormalities
4.1.4.1. mTERC
5. Uterine Mesenchymal Tumors
5.1. Leiomyoma
5.1.1. Model presenting with leiomyoma
5.2. Leiomyosarcoma
5.2.1. Models presenting with leiomyosarcoma
5.2.1.1. CaBP9k/Tag
5.2.1.2. mogp-Tag
5.2.1.3. Beta-actin SVER/+/HS-cre1
5.2.1.4. MMTV-CR-1
5.2.1.5. LMP2
5.2.1.6. E2F-1
5.3. Endometrial stromal sarcoma
5.3.1. Models presenting with lesions resembling endometrial stromal sarcoma
5.3.1.1. p53val135/w
5.3.1.2. p53+/- CBA
6. Other Uterine Tumors
6.1. MMTV betaTcrp1
7. Utility of Mouse Models in Studying Human Disease
8. Current and Proposed Criteria for Describing Tumor Pathology in Mutant Mouse Models
9. Perspective
10. Acknowledgements
11. References

1. ABSTRACT

Uterine tumors, whether benign or malignant, are diagnosed in a significant portion of women and are associated with a number of co-morbidities that negatively impact quality of life. Uterine tumors can be derived from the epithelial (endometrial hyperplasia or carcinoma) and mesenchymal (leiomyoma, sarcoma) layers of the uterus. The exact etiologies of the various tumor types are yet to be defined. Collectively their development and progression often results from aberrant steroid hormone exposure or dysregulation of related growth factor signaling and apoptotic pathways, reflecting the role of steroid hormone-dependent signaling and survival pathways in the cycles of cell growth and involution that characterize normal uterine physiology. While molecular analyses of human tumors can identify candidate genetic and epigenetic lesions contributing to uterine tumor initiation and progression, in vivo genetic models are needed to establish the functional significance of such lesions and their contribution to tumorigenesis. For this purpose, genetically-engineered mouse models have proven valuable. Here we review genetically-modified mouse models that develop uterine tumors and compare their pathology, utility/feasibility, and discuss their clinical relevance.