Animal Model Progression to Malignancy in the Polyoma Middle T Oncoprotein Mouse Breast Cancer Model Provides a Reliable Model for Human Diseases Elaine Y. Lin,* Joan G. Jones, † Ping Li,* Liyin Zhu,* Kathleen D. Whitney, † William J. Muller, ‡ and Jeffrey W. Pollard* From the Center for Study of Reproductive Biology and Women’s Health and the Departments of Developmental and Molecular Biology and Obstetrics and Gynecology and Women’s Health,* and the Department of Pathology, † Albert Einstein College of Medicine, Bronx, New York; and the Department of Medicine and Biochemistry, ‡ McGill University, Montreal, Quebec, Canada Animal models are powerful tools to analyze the mechanism of the induction of human breast cancer. Here we report a detailed analysis of mammary tumor progression in one mouse model of breast cancer caused by expression of the polyoma middle T onco- protein (PyMT) in the mammary epithelium , and its comparison to human breast tumors. In PyMT mice , four distinctly identifiable stages of tumor progres- sion from premalignant to malignant stages occur in a single primary tumor focus and this malignant tran- sition is followed by a high frequency of distant me- tastasis. These stages are comparable to human breast diseases classified as benign or in situ proliferative lesions to invasive carcinomas. In addition to the morphological similarities with human breast can- cer , the expression of biomarkers in PyMT-induced tumors is also consistent with those associated with poor outcome in humans. These include a loss of estrogen and progesterone receptors as well as inte- grin-1 expression and the persistent expression of ErbB2/Neu and cyclinD1 in PyMT-induced tumors as they progress to the malignant stage. An increased leukocytic infiltration was also closely associated with the malignant transition. This study demon- strates that the PyMT mouse model is an excellent one to understand the biology of tumor progression in humans. (Am J Pathol 2003, 163:2113–2126) Breast cancer has the highest incidence among women in the Western world affecting up to 10% of women in the future and therefore is among today’s most pressing health problems. 1 Despite improvements in diagnosis, treatment, and longevity, the effect on mortality has been modest. 1 A lack of understanding about the natural his- tory of the disease is a major contributory factor to this limitation. 2 On a molecular level it is still unclear which of the changes in breast tumors are likely to lead to invasion and metastasis. The application of transgenic technology in mice to study the progression of mammary cancer has proven extremely powerful to understand important prin- ciples of tumorigenesis and evaluating response to ther- apy. 3–6 However, few of these models reflect the com- plexity of human breast cancers, especially their progression to metastasis. Previously we have reported that we chose one of the breast cancer transgenic mouse models whose onco- genesis is induced by expression of the polyoma virus middle T oncoprotein (PyMT mice) to study the effect of the mononuclear phagocyte growth factor, colony-stimu- lating factor-1 (CSF-1) in mammary tumor progression. 7 In this model, the expression of the oncoprotein, polyoma middle T antigen (PyMT), is under the control of mouse mammary tumor virus LTR (MMTV LTR) and is therefore restricted to the mammary epithelium. Mammary hyper- plasia can be detected in this model as early as 4 weeks 7,8 and most importantly, a large percentage of mice developed carcinoma at 14 weeks and this cor- related with the appearance of pulmonary metastases. 7 PyMT, a membrane-attached protein, is encoded by the small DNA polyoma virus. PyMT is not expressed in hu- man breast tumor cells, however, it acts as a potent Supported by the Analytical Imaging Facility and Histotechnology and Comparative Pathology Facility at Albert Einstein College of Medicine; the Albert Einstein College Comprehensive Cancer Center (P30-CA13330), and the National Institutes of Health (RO1CA094173). JWP is the Sheldon and Betty E. Feinberg Senior Faculty Scholar in Cancer Research and EYL was a recipient of National Research Service Award 5-T32-AG00194. Accepted for publication July 28, 2003. Address reprint requests to Jeffrey W. Pollard, 607 Chanin Building, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: pollard@aecom.yu.edu. American Journal of Pathology, Vol. 163, No. 5, November 2003 Copyright © American Society for Investigative Pathology 2113