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[Cancer Research 64, 3525-3532, May 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Somatic Mutation of p53 Leads to Estrogen Receptor {alpha}-Positive and -Negative Mouse Mammary Tumors with High Frequency of Metastasis

Suh-Chin J. Lin1,2, Kuo-Fen Lee4, Alexander Yu. Nikitin5, Susan G. Hilsenbeck6, Robert D. Cardiff7, Aihua Li1,2, Keon-Wook Kang1,2, Steven A. Frank3, Wen-Hwa Lee2 and Eva Y-H. P. Lee1,2

1 Departments of Developmental and Cell Biology, 2 Biological Chemistry, and 3 Ecology and Evolutionary Biology, University of California, Irvine, California; 4 The Salk Institute for Biological Studies, La Jolla, California; 5 Department of Biomedical Sciences, Cornell University, Ithaca, New York; 6 Department of Medicine and Department of Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, Texas; and 7 Center for Comparative Medicine, University of California, Davis, California

Approximately 70% of human breast cancers are estrogen receptor {alpha} (ER{alpha})-positive, but the origins of ER{alpha}-positive and -negative tumors remain unclear. Hormonal regulation of mammary gland development in mice is similar to that in humans; however, most mouse models produce only ER{alpha}-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report here that somatic mutations of p53 in mouse mammary epithelial cells using the Cre/loxP system leads to ER{alpha}-positive and -negative tumors. p53 inactivation under a constitutive active WAPCrec in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ER{alpha}-positive tumors, suggesting that target cells or developmental stages can determine ER{alpha} status in mammary tumors. Importantly, these tumors have a high rate of metastasis. An inverse relationship between the number of targeted cells and median tumor latency was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Thus, this tumor system reproduces many important features of human breast cancer and provides tools for the study of the origins of ER{alpha}-positive and -negative breast tumors in mice.




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