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Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

Oncogene volume 21, pages 108–118 (2002)Cite this article

Abstract

To characterize the impact of increased production of TGF-β in a xenograft model of human breast cancer, TGF-β-responsive MDA-231 cells were genetically modified by stable transfection so as to increase their production of active TGF-β1. Compared with control cells, cells that produced increased amounts of TGF-β proliferated in vitro more slowly. In vivo, however, tumors derived from these cells exhibited increased proliferation and grew at an accelerated pace. To evaluate the role of autocrine TGF-β signaling, cells were also transfected with a dominant-negative truncated type II TGF-β receptor (TβRII). Disruption of autocrine TGF-β signaling in the TGF-β-overexpressing cells reduced their in vivo growth rate. Co-inoculation of Matrigel with the TGF-β-overexpressing cells expressing the truncated TβRII compensated for their diminished in vivo growth capacity, compared with the TGF-β-overexpressing cells with an intact autocrine loop. Tissue invasion by the tumor was a distinctive feature of the TGF-β-overexpressing cells, whether or not the autocrine loop was intact. Furthermore, tumors derived from TGF-β-overexpressing cells, irrespective of the status of the autocrine TGF-β-signaling pathway, had a higher incidence of lung metastasis. Consistent with the suggestion that TGF-β's enhancement of invasion and metastasis is paracrine-based, we observed no significant differences among the cell clones in an in vitro invasion assay. Thus, in this experimental model system in vitro assays of cell proliferation and invasion do not accurately reflect in vivo observations, perhaps due to autocrine and paracrine effects of TGF-β that influence the important in vivo-based phenomena of tumor growth, invasion, and metastasis.

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Acknowledgements

We thank Dr Harvey Lodish and colleagues for the TβR-II cDNA clone H2-3FF, Dr John E Majors for the pCEN/MER plasmid, and Dr Dan Rifkin for the p800LUC plasmid and the stably transfected mink lung epithelial cells. Maudine Waterman provided expert assistance with the immunohistochemical analysis. This research was supported by grants CA60928 from the National Cancer Institute and DAMD17-94-J-4130 from the Department of Defense Breast Cancer Research Program. Dr Tobin was supported by National Cancer Institute Training Grant CA09658. This publication is dedicated to the memory of Lisa Deslandes.

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  1. Stephen W Tobin

    Present address: Department of Biology, Saint Anselm College, Manchester, 03102, New Hampshire, NH, USA

Authors and Affiliations

  1. Department of Medicine, Dartmouth Medical School, Hanover, 03755, New Hampshire, NH, USA

    Karen Douville, Ulrike Benbow, Constance E Brinckerhoff & Bradley A Arrick

  2. Department of Biochemistry, Dartmouth Medical School, Hanover, 03755, New Hampshire, NH, USA

    Stephen W Tobin & Constance E Brinckerhoff

  3. Department of Pathology, Dartmouth Medical School, Hanover, 03755, New Hampshire, NH, USA

    Vincent A Memoli

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Correspondence to Bradley A Arrick.

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Tobin, S., Douville, K., Benbow, U. et al. Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects. Oncogene 21, 108–118 (2002). https://doi.org/10.1038/sj.onc.1205026

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