Davidoff A M, Humphrey P A, Iglehart J D, Marks J R
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):5006-10. doi: 10.1073/pnas.88.11.5006.
Overexpression of an activated form of the p53 protein may be involved in neoplastic transformation. We found widespread overexpression of p53 by immunohistochemical staining in 11 (22%) of 49 primary invasive human breast cancers. Northern blot analysis showed that this overexpression was not due to an increase in the steady-state level of p53 mRNA. The p53 gene was directly sequenced in 7 of these tumors with elevated levels of the protein and, in each case, a mutation that altered the coding sequence for p53 was found in a highly conserved region of the gene. Whereas 4 of these tumors contained only a mutant p53 allele, the other 3 tumors exhibited coding sequences from both a mutant and a wild-type allele. p53 mutations have previously been correlated with allelic loss of part of chromosome 17p that contains the p53 locus. Examination of all 49 breast tumors revealed a 61% frequency of deletion at or near the p53 locus. However, the presence of allelic deletion did not correlate with overexpression of the protein. Six tumors that were deleted but did not express high levels of the protein were sequenced and all retained a wild-type p53 allele. In this series of human breast cancers, overexpression of the p53 protein, not allelic loss on chromosome 17p, was always associated with mutation of the p53 gene.
p53蛋白激活形式的过表达可能参与肿瘤转化。我们通过免疫组织化学染色发现，49例原发性浸润性人类乳腺癌中有11例（22%）存在广泛的p53过表达。Northern印迹分析表明，这种过表达并非由于p53 mRNA稳态水平的增加。对其中7例蛋白水平升高的肿瘤进行了p53基因直接测序，在每例肿瘤中，均在该基因的高度保守区域发现了改变p53编码序列的突变。其中4例肿瘤仅含有突变的p53等位基因，而其他3例肿瘤则同时显示出突变等位基因和野生型等位基因的编码序列。p53突变以前曾与包含p53基因座的17号染色体短臂部分的等位基因缺失相关。对所有49例乳腺肿瘤的检查显示，p53基因座或其附近的缺失频率为61%。然而，等位基因缺失的存在与蛋白的过表达并无关联。对6例发生缺失但未表达高水平蛋白的肿瘤进行了测序，所有肿瘤均保留了野生型p53等位基因。在这一系列人类乳腺癌中，p53蛋白的过表达而非17号染色体短臂上的等位基因缺失，总是与p53基因的突变相关。
