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[Cancer Research 65, 2296-2302, March 15, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Effect of Conditional Knockout of the Type II TGF-ß Receptor Gene in Mammary Epithelia on Mammary Gland Development and Polyomavirus Middle T Antigen Induced Tumor Formation and Metastasis

Elizabeth Forrester1, Anna Chytil1,3, Brian Bierie1, Mary Aakre1,3, Agnieszka E. Gorska1,3, Ali-Reza Sharif-Afshar1, William J. Muller4 and Harold L. Moses1,2,3

Departments of 1 Cancer Biology and 2 Medicine; 3 Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; and 4 Departments of Medicine and Biochemistry, McGill University, Montreal, Quebec, Canada

Requests for reprints: Harold L. Moses, Department of Cancer Biology, Ingram Cancer Center, Vanderbilt University School of Medicine, 698 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6838. Phone: 615-936-1782; Fax: 615-936-1790; E-mail: hal.moses{at}vanderbilt.edu.

Transforming growth factor–ß (TGF-ß) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-ß signaling in mammary tumorigenesis is complex, as TGF-ß has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-ß signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-ß receptor, Tgfbr2, was conditionally deleted in the mammary epithelium (Tgfbr2MGKO). Loss of Tgfbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2MGKO mice were mated to the mouse mammary tumor virus-polyomavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of Tgfbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-ß signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-ß signaling in the carcinoma cells.

Key Words: TGF-ß • polyomavirus • Cre-Lox • mammary gland • metastasis




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