AFFINITY FOR THE INSULIN-LIKE GROWTH FACTOR-II (IGF-II) RECEPTOR INHIBITS AUTOCRINE IGF-II ACTIVITY IN MCF-7 BREAST-CANCER CELLS

We have investigated the autocrine regulation of insulin-like growth f actor-II (IGF-II) signaling by the insulin-like growth factor-I recept or (IGF-IR) and the insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-IIR) in MCF-7 breast cancer cells, employing retroviruse s encoding both IGF-I, IGF-II, and IGF-I and II mutants with reduction s in affinity for either the IGF-IR or the IGF-IIR, These studies reve aled reciprocal roles for IGF-IR and IGF-IIR affinity in the regulatio n of autocrine IGF-II activity, IGF-IR affinity was required for serum -free proliferation but also for efficient IGF-II secretion, In contra st, cellular proliferation, receptor tyrosine kinase-dependent signali ng, and extracellular IGF-II protein accumulation were all reduced in the presence of IGF-IIR affinity, Inhibition of IGF-II signaling appea red to be the sole consequence of IGF-IIR affinity, as no cellular res ponses attributable to selective IGF-IIR binding by a reduced IGF-IR a ffinity IGF-II mutant could be detected, By operating as an IGF-II ant agonist, the IGF-IIR has tumor suppressor-like properties, a suggestio n consistent with reports of loss of heterozygosity at the IGF-IIR loc us in a variety of human malignancies.