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

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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

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Transforming Growth Factors
Breast Neoplasms
Neoplasm Metastasis
Doxycycline
Polyomavirus Transforming Antigens
Neoplasms
Smad2 Protein
Nuclear Proteins
Transgenic Mice
Cell Movement
Cell Survival
Cell Proliferation
Lung
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors. / Muraoka-Cook, Rebecca S.; Kurokawa, Hirokazu; Koh, Yasuhiro; Forbes, James T.; Roebuck, L. Renee; Barcellos-Hoff, Mary Helen; Moody, Susan E.; Chodosh, Lewis A.; Arteaga, Carlos L.

In: Cancer Research, Vol. 64, No. 24, 15.12.2004, p. 9002-9011.

Research output: Contribution to journalArticle

Muraoka-Cook, RS, Kurokawa, H, Koh, Y, Forbes, JT, Roebuck, LR, Barcellos-Hoff, MH, Moody, SE, Chodosh, LA & Arteaga, CL 2004, 'Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors', Cancer Research, vol. 64, no. 24, pp. 9002-9011. https://doi.org/10.1158/0008-5472.CAN-04-2111
Muraoka-Cook, Rebecca S. ; Kurokawa, Hirokazu ; Koh, Yasuhiro ; Forbes, James T. ; Roebuck, L. Renee ; Barcellos-Hoff, Mary Helen ; Moody, Susan E. ; Chodosh, Lewis A. ; Arteaga, Carlos L. / Conditional overexpression of active transforming growth factor β1 in vivo accelerates metastases of transgenic mammary tumors. In: Cancer Research. 2004 ; Vol. 64, No. 24. pp. 9002-9011.
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