Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors

Rebecca S. Muraoka-Cook, Hirokazu Kurokawa, Yasuhiro Koh, James T. Forbes, L. Renee Roebuck, Mary Helen Barcellos-Hoff, Susan E. Moody, Lewis A. Chodosh, Carlos L. Arteaga

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

To address the role of transforming growth factor (TGF) β in the progression of established tumors while avoiding the confounding inhibitory effects of TGF-β on early transformation, we generated doxycycline (DOX)-inducible triple transgenic mice in which active TGF-β1 expression could be conditionally regulated in mouse mammary tumor cells transformed by the polyomavirus middle T antigen. DOX-mediated induction of TGF-β1 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-β1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-β and increased metastases. Antisense-mediated inhibition of TGF-β1 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-β in hosts with established TGF-β-responsive cancers can rapidly accelerate metastatic progression.

Original languageEnglish (US)
Pages (from-to)9002-9011
Number of pages10
JournalCancer research
Volume64
Issue number24
DOIs
StatePublished - Dec 15 2004

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Muraoka-Cook, R. S., Kurokawa, H., Koh, Y., Forbes, J. T., Roebuck, L. R., Barcellos-Hoff, M. H., Moody, S. E., Chodosh, L. A., & Arteaga, C. L. (2004). Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors. Cancer research, 64(24), 9002-9011. https://doi.org/10.1158/0008-5472.CAN-04-2111