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-
TGFbeta 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 --> Ala) was in BG1
ovarian-cancer cells, and was due to an A-to-G substitution on one allele at
nucleotide 2561. 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 over-expression of some of its
ligands, might be sufficient to saturate the receptor
protein, displace the
ligands to other sites, and consequently facilitate
tumor progression.