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

Abstract

Summary 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)-f,. 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 ERpositive 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-fl, and TGF-fl2 measured using a quantitative immunoassay. Fibroblast strains derived from malignant and benign tumours produced and secreted similar amounts of TGF-flp, but benign breast tumour fibroblasts secreted significantly higher levels of TGF-f32 compared with fibroblasts of malignant origin. Tamoxifen did not induce any consistent increase in TGF-,B secretion into the conditioned medium, but immunofluorescence analysis for the intracellular form of TGF-f3, revealed evidence of increased immunoreactive protein in tamoxifen-treated fibroblasts, which is localised to the nucleus. Therefore synthesis of TGF-fl, 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.

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

“…33 Although diseased NAME rats overexpressed PAI-1 mRNA, tamoxifen treatment induced a marked downregulation of PAI-1 in renal tissue. PAI-1 inhibition associated with tamoxifen treatment may contribute to amelioration of ECM turnover.…”

“…In contrast, some tumor cell lines and breast cancer cells have a different response to tamoxifen, consisting of an increase in TGF-b production. 32,33 Thus, the exact mechanisms involved in these discordant effects have not been completely clarified.…”

Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21waf1/cip1

“…Tamoxifen has been shown to increase TGF-␤ secretion in breast cancer cells [18,19], as well as in supporting stromal cells [22]. Tamoxifen inhibits the Ca 2+ /phospholipid-dependent activity of PKC in vitro, with IC 50 s as low as 6.1 M [23]; efficacy in vivo may be greater [20].…”

Gossypol inhibits the growth of MAT-LyLu prostate cancer cells by modulation of TGFβ/Akt signaling

“…Experimental data suggest that GP may affect cell cycle distribution by modulating the expression of transforming growth factor ß1 (TGFß1) and cell cycle regulator cyclin D1 in prostate cancer cells (6,9) suggesting the involvement of TGFß1 in GP-induced growth inhibition. TGFß1 has been shown to mediate the antiproliferative effects of many antitumor agents, including vitamin D 3 (17), genistein (18), GP (6,9) and tamoxifen (19). TGFß1 exerts its biological effects by binding to TGFß receptor II (TßRII), which induces formation of a heteromeric complex of TßRII and TßRI, triggering a signaling pathway that regulates cell cycle regulators such as Rb, cyclin and cyclin-dependent kinase (20,21).…”