Abstract
The mannose-6-phosphate/insulin-like growth factor 2 receptor (Man-6-P/IGFII receptor) is involved in lysosomal enzyme sorting, IGFII degradation and pro-TGF beta activation. Genetic alterations in hepatocarcinomas and a few breast cancers suggest that this receptor behaves as a tumor suppressor. Moreover, hypersecretion and Man-6-P-independent targeting of cathepsins in breast and ovarian carcinomas also suggest alterations in this receptor. We studied the Man-6-P/IGFII receptor gene in 8 ovarian carcinomas, and 4 breast- and ovarian-cancer cell lines. The results confirmed a frequent loss of heterozygosity (LOH) in the 6q27-qter region in 5 out of 8 ovarian carcinomas, We used 23 overlapping RT-PCR fragments to sequence the whole coding region of the Man-6-P/IGFII receptor. The 2491 amino-acid sequence of this receptor was perfectly conserved in 9 out of 10 of our samples, including MCF7 and MDA-MB231 cells and 5 ovarian carcinomas with LOH, This allowed us to rectify the 2 previously published sequences which differed in several bases, and to propose a consensus amino-acid sequence. The only amino-acid change (Thr \textendash\textgreater Ala) was in BGI ovarian-cancer cells, and was due to an A-to-G substitution on one allele at nucleotide 256I. We found no bi-allelic alterations in the 9 ovarian carcinomas, but 3 silent nucleotide substitutions leading to a lower cordon usage in 2 ovarian carcinomas with LOH, No mutation of the Man-6-P/IGFII receptor coding sequence was found in breast-cancer cell lines to explain the cathepsin-D hypersecretion and Man-6-P-independent trafficking described. We propose that, in breast and ovarian cancers, the frequent loss of one allele, associated with overexpression of some of its ligands, might be sufficient to saturate the receptor protein, displace the ligands to other sites, and consequently facilitate tumor progression. Int. J. Cancer 85:466-473, 2000, (C) 2000 Wiley-Liss, Inc.