ANDROGEN-INDUCED GROWTH-FACTOR AND ITS RECEPTOR - DEMONSTRATION OF THE ANDROGEN-INDUCED AUTOCRINE LOOP IN MOUSE MAMMARY-CARCINOMA CELLS

SC-3 cells derived from mouse mammary carcinoma (Shionogi carcinoma 11 5) exhibit remarkable growth enhancement and cell morphology change in response to androgen stimuli. These events are mediated through an an drogen-induced growth factor (AIGF). Amino acid sequence deduced from cDNA reveals that AIGF has 215 amino acids with a signal peptide and s cattered regions homologous to fibroblast growth factor (FGF) family p roteins. The biological ability of AIGF to stimulate SC-3 cell growth is inhibited by heparin or suramin. More importantly, antisense oligod eoxynucleotide of AIGF can block androgen-induced growth of SC-3 cells . Upon synthesis under the control of androgen, AIGF is immediately se creted into the extracellular space without intracellular accumulation . At the early phase (18-24 h) of androgen stimulation, however, AIGF is mainly associated with the glycosaminoglycan on the cell surface or extracellular matrix. In addition, treatment of SC-3 cells with sulfa tion blocker (chlorate) or heparitinase results in the abolishment of their ability to respond to androgen or AIGF, indicating that heparan sulfate has important robs for condensing AIGF on or near the cell sur face as well as potentiating the biological activity of AIGF. Then, AI GF can bind to the FGF receptor. Northern blot analysis and cDNA cloni ng indicate that SC-3 cells predominantly express the FGF receptor I w ith some altered amino acid sequences. Transfection of expression vect ors of AIGF and this variant form of FGF receptor 1 into FGF receptor- negative myoblast cells (L 6 cells) confirms that a variant form of FG F receptor 1 is a receptor of AIGF. These results clearly demonstrate that an autocrine mechanism is operating in androgen-induced growth of SC-3 cells.