Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen

Br J Cancer. 1996 Aug;74(3):352-8. doi: 10.1038/bjc.1996.365.


Tamoxifen may mediate its effect in early breast cancer in part via an oestrogen receptor (ER)-independent pathway by directly stimulating fibroblasts to produce the negative paracrine growth factor transforming growth factor (TGF)-beta. We have previously shown that secretion of this factor is induced 3-to 30-fold in human fetal fibroblasts in vitro, and by stromal fibroblasts in vivo following tamoxifen treatment of ER-positive and ER-negative breast cancer patients. Primary cultures of breast tumour fibroblasts have been exposed to tamoxifen for 48 h, and rates of secretion of TGF-beta 1 and TGF-beta 2 measured using a quantitative immunoassay. Fibroblast strains derived from malignant and benign tumours produced and secreted similar amounts of TGF-beta 1, but benign breast tumour fibroblasts secreted significantly higher levels of TGF-beta 2 compared with fibroblasts of malignant origin. Tamoxifen did not induce any consistent increase in TGF-beta secretion into the conditioned medium, but immunofluorescence analysis for the intracellular form of TGF-beta 1 revealed evidence of increased immunoreactive protein in tamoxifen-treated fibroblasts, which is localised to the nucleus. Therefore synthesis of TGF-beta 1 appears to be stimulated by tamoxifen, but increased secretion may be abrogated in vitro. Furthermore, using immunocytochemistry and transient transfection with an ER-responsive reporter construct, no ER was demonstrable in these fibroblasts supporting the proposed ER-independent paracrine pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Breast Neoplasms / metabolism*
  • Cells, Cultured
  • Female
  • Fibroblasts / metabolism
  • Fluorescent Antibody Technique
  • Humans
  • Receptors, Estrogen / analysis
  • Tamoxifen / pharmacology*
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / biosynthesis*
  • Transforming Growth Factor beta / metabolism


  • Antineoplastic Agents, Hormonal
  • Receptors, Estrogen
  • Transforming Growth Factor beta
  • Tamoxifen