Tumor Formation and Metastasis Development and Polyomavirus Middle T Antigen Induced Gene in Mammary Epithelia on Mammary Gland

Transforming growth factor–B (TGF-B) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-B signaling in mammary tumorigenesis is complex, as TGF-B has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-B signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-B receptor, Tgfbr2 , was conditionally deleted in themammary epithelium (Tgfbr2). Loss of Tgfbr2 in the mammary epithelium results in lobularalveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2 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 tumorsuppressive role for epithelial TGF-B signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-B signaling in the carcinoma cells. (Cancer Res 2005; 65(6): 2296-302)