INSULIN-LIKE GROWTH-FACTORS (IGFS) STIMULATE THE RELEASE OF ALPHA-1-ANTICHYMOTRYPSIN AND SOLUBLE IGF-II MANNOSE 6-PHOSPHATE RECEPTOR FROM MCF7 BREAST-CANCER CELLS/

The growth of hormone-responsive MCF7 human breast cancer cells is con trolled by steroid hormones and growth factors. By metabolic labeling of cells grown in steroid- and growth factor-stripped serum conditions , we show that insulin-like growth factors (IGF-I and IGF-II) increase by approximately 5-fold the release of several proteins including cat hepsin D, alpha(1)-antichymotrypsin, and soluble forms of the multifun ctional IGF-II/mannose 6-phosphate (M6P) receptor. Two soluble forms o f IGF-II/M6P receptors were detected, one major (approximate to 260 ki lodaltons) and one minor (approximate to 85 kilodaltons) that probably represents a proteolytic fragment of the larger soluble molecule. IGF s increased receptor release in a dose-dependent fashion with 50-60% o f newly synthesized receptor released at 5-10 nM IGFs. The release of IGF-II/M6P receptors correlated with the levels of secreted cathepsin D in different human breast cancer cells or in rat stable transfectant s that are constitutively expressing variable levels of human cathepsi n D. IGFs had a stronger effect on IGF-II/M6P receptor release, wherea s estradiol treatment preferentially enhanced the release of protease and antiprotease. We thus demonstrate that in human breast cancer cell s, IGFs not only act as strong mitogens but also regulate release of a lpha(1)-antichymotrypsin, IGF-II/M6P-soluble receptor, and cathepsin D ; three proteins that potentially regulate cell proliferation and/or i nvasion.