M6P/IGF2 receptor: a candidate breast tumor suppressor gene.
M6P/IGF2 receptor: a candidate breast tumor suppressor gene.
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发表时间：
1996-05
期刊：
影响因子：
8
通讯作者：
Hankins Gr;Denisov At;Rex C. Bentley;Patel Mr;Marks;Iglehart Jd;R. Jirtle
中科院分区：
文献类型：
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作者：
Hankins Gr;Denisov At;Rex C. Bentley;Patel Mr;Marks;Iglehart Jd;R. Jirtle
甘露糖6-磷酸/胰岛素样生长因子2受体（M6P/IGF2r）在TGF β（大多数细胞类型的有效生长抑制剂）的活化、有丝分裂原IGF2的降解和溶酶体酶的细胞内运输中发挥作用。我们发现它的表达在大鼠和人肝细胞癌（HCC）中显著降低，并且最近报道了该基因座的杂合性丢失（洛）以及人肝肿瘤中剩余等位基因的突变。应用聚合酶链反应技术，我们利用M6 P/IGF 2 r基因3 '端非翻译区的两个多态性来筛选乳腺肿瘤的洛。62例患者中有40例（65%）为杂合子，12/40例（30%）乳腺肿瘤有洛，5/19例（26%）原位癌（CIS）和7/21例（33%）浸润性癌。为了研究乳腺癌发生的早期分子遗传学事件，我们筛选了具有洛缺失的CIS突变。在这些肿瘤的2/5（40%）中，在剩余的等位基因中发现了错义突变，引起了显著的氨基酸取代。这些发现提供了证据表明，M6P/IGF2r等位基因丢失是乳腺癌病因学中的早期事件，该基因在乳腺中起肿瘤抑制基因的作用。
The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) functions in the activation of TGFbeta, a potent growth inhibitor for most cell types, the degradation of the mitogen, IGF2, and the intracellular trafficking of lysosomal enzymes. We have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs) and recently reported loss of heterozygosity (LOH) at this locus with mutations in the remaining allele in human liver tumors. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of M6P/IGF2r to screen breast tumors for 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 molecular genetic events in breast carcinogenesis, we screened the CIS with LOH for mutations. In 2/5 (40%) of these tumors, missense mutations were found in the remaining allele that gave rise to significant amino acid substitutions. These findings provide evidence that M6P/IGF2r allelic loss is an early event in the etiology of breast cancer, that this gene functions as a tumor suppressor gene in the breast.