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Conditional Overexpression of Active Transforming Growth Factor ß1 In vivo Accelerates Metastases of Transgenic Mammary Tumors

Departments of ¹ Cancer Biology and ² Medicine and ³ Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Departments of ⁴ Cancer Biology and Medicine and ⁵ Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ⁶ Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California

To address the role of transforming growth factor (TGF) ß in the progression of established tumors while avoiding the confounding inhibitory effects of TGF-ß on early transformation, we generated doxycycline (DOX)-inducible triple transgenic mice in which active TGF-ß1 expression could be conditionally regulated in mouse mammary tumor cells transformed by the polyomavirus middle T antigen. DOX-mediated induction of TGF-ß1 for as little as 2 weeks increased lung metastases >10-fold without a detectable effect on primary tumor cell proliferation or tumor size. DOX-induced active TGF-ß1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-ß and increased metastases. Antisense-mediated inhibition of TGF-ß1 in polyomavirus middle T antigen-expressing tumor cells also reduced basal cell motility, survival, anchorage-independent growth, tumorigenicity, and metastases. Therefore, induction and/or activation of TGF-ß in hosts with established TGF-ß-responsive cancers can rapidly accelerate metastatic progression.

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