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

Oncogene. 2002 Jan 3;21(1):108-18. doi: 10.1038/sj.onc.1205026.

Abstract

To characterize the impact of increased production of TGF-beta in a xenograft model of human breast cancer, TGF-beta-responsive MDA-231 cells were genetically modified by stable transfection so as to increase their production of active TGF-beta1. Compared with control cells, cells that produced increased amounts of TGF-beta 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-beta signaling, cells were also transfected with a dominant-negative truncated type II TGF-beta receptor (TbetaRII). Disruption of autocrine TGF-beta signaling in the TGF-beta-overexpressing cells reduced their in vivo growth rate. Co-inoculation of Matrigel with the TGF-beta-overexpressing cells expressing the truncated TbetaRII compensated for their diminished in vivo growth capacity, compared with the TGF-beta-overexpressing cells with an intact autocrine loop. Tissue invasion by the tumor was a distinctive feature of the TGF-beta-overexpressing cells, whether or not the autocrine loop was intact. Furthermore, tumors derived from TGF-beta-overexpressing cells, irrespective of the status of the autocrine TGF-beta-signaling pathway, had a higher incidence of lung metastasis. Consistent with the suggestion that TGF-beta'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-beta that influence the important in vivo-based phenomena of tumor growth, invasion, and metastasis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autocrine Communication*
  • Breast Neoplasms / complications
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / complications
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Ductal, Breast / secondary
  • Cell Division
  • Collagen
  • Culture Media, Conditioned / pharmacology
  • Drug Combinations
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, Dominant
  • Hemorrhage / etiology
  • Humans
  • Laminin
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplasm Transplantation
  • Paracrine Communication*
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases
  • Proteoglycans
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / drug effects
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / metabolism
  • Sequence Deletion
  • Skin Ulcer / etiology
  • Transfection
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology

Substances

  • Culture Media, Conditioned
  • Drug Combinations
  • Laminin
  • Neoplasm Proteins
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Transforming Growth Factor beta
  • matrigel
  • Collagen
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II