Increased expression of the mannose 6‐phosphate/insulin‐like growth factor‐II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivo

The mannose 6‐phosphate/insulin‐like growth factor‐II receptor (M6P/IGF‐IIR) is thought to act as a suppressor of tumor growth by binding the mitogenic peptide IGF‐II and modulating its extracellular levels via degradation. This receptor has been found to be absent or nonfunctional in a high proportion of breast tumors as a result of LOH and mutation of the gene. In our study, we have examined the effect of increasing expression of M6P/IGF‐IIR on breast cancer cell tumorigenicity. MDA‐MB‐231 breast cancer cells stably transfected with M6P/IGF‐IIR cDNA exhibited not only a greatly reduced ability to form tumors but also a markedly reduced growth rate in nude mice. In vitro , increased M6P/IGF‐IIR expression resulted in 2‐fold reduced uptake of IGF‐II and was associated with reduced cellular invasiness and motility. Cells with increased M6P/IGF‐IIR expression exhibited reduced phosphorylation of IGF‐I receptor and p44/42 MAPK compared to vector transfectants, or wild‐type MDA‐MB‐231 cells. These results therefore suggest that M6P/IGF‐IIR levels can modulate breast cancer cell tumorigenicity by a mechanism that may involve altered IGF‐I receptor signaling. © 2003 Wiley‐Liss, Inc.