M6P IGF2 RECEPTOR - A CANDIDATE BREAST-TUMOR SUPPRESSOR GENE/

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF 2r) functions in the activation of TGF beta, a potent growth inhibitor for most cell types, the degradation of the mitogen, IGF2, and the in tracellular trafficking of lysosomal enzymes, We have found its expres sion to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs) and recently reported loss of heterozygosity (LOH) a t this locus with mutations in the remaining allele in human liver tum ors, Using the polymerase chain reaction, we utilized two polymorphism s in the 3' untranslated region of M6P/IGF2r to screen breast tumors f or LOH, Forty of 62 (65%) patients were informative (heterozygous) and 12/40 (30%) breast tumors had LOH; 5/19 (26%) carcinomas in situ (CIS ) and 7/21 (33%) invasive carcinomas, To investigate the early molecul ar genetic events in breast carcinogenesis, we screened the CIS with L OH for mutations, In 2/5 (40%) of these tumors, missense mutations wer e found in the remaining allele that gave rise to significant amino ac id substitutions. These findings provide evidence that M6P/IGF2r allel ic loss is an early event in the etiology of breast cancer, and that t his gene functions as a tumor suppressor gene in the breast.