ASSOCIATION OF P53 PROTEIN EXPRESSION WITH TUMOR-CELL PROLIFERATION RATE AND CLINICAL OUTCOME IN NODE-NEGATIVE BREAST-CANCER
ASSOCIATION OF P53 PROTEIN EXPRESSION WITH TUMOR-CELL PROLIFERATION RATE AND CLINICAL OUTCOME IN NODE-NEGATIVE BREAST-CANCER
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DOI：
10.1093/jnci/85.3.200
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发表时间：
1993-02-03
期刊：
影响因子：
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通讯作者：
MCGUIRE, WL
中科院分区：
文献类型：
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作者：
ALLRED, DC;CLARK, GM;MCGUIRE, WL
背景：p53（也称为TP53）肿瘤抑制基因编码一种被认为调节正常细胞增殖的核磷酸化蛋白。大多数p53突变导致在肿瘤细胞核中积累的无功能蛋白。这些常见的突变似乎与包括人类乳腺癌在内的几种肿瘤疾病的发生和/或进展有关。目的：我们的目的是探讨突变型p53蛋白表达水平、肿瘤细胞增殖率和淋巴结阴性乳腺癌患者临床转归之间的关系。方法：对700例腋淋巴结阴性乳腺癌患者进行长期随访（中位54个月），采用冷冻切片免疫组化（IHC）和光镜检测突变型p53蛋白的表达。免疫染色信号用表示阴性和阳性肿瘤细胞核比例和染色强度的分数之和表示（范围分别为0和2-8）。通过流式细胞术测定p53蛋白表达水平与无病生存期、总生存期和以S期细胞百分比（%S期）表示的肿瘤增殖率之间进行统计学比较。结果：700例肿瘤中，核免疫染色阳性362例（52%）（IHC评分bb0 0）。阳性肿瘤（中位%S期，7.1%）的增殖率显著高于阴性肿瘤（4.1%）（P = 0.0001）。在单变量临界点分析中，阴性肿瘤（n = 388）与低阳性肿瘤（IHC评分为2-6；n = 263）相比，高阳性肿瘤（IHC评分为bbb6； n = 99）的无病生存率逐渐降低(5年分别为80%对72%对58%；P小于或等于。所有两两比较为0.05)。总生存率的类似结果为88%对84%对74%；只有阴性肿瘤和高阳性肿瘤的结果有统计学意义（P = 0.003）。在多变量分析中，p53蛋白表达和高%S期与无病生存期降低独立相关（P = 0.008和P = 0.008）。分别为01)。结论：突变型p53蛋白的表达与淋巴结阴性乳腺癌的高肿瘤增殖率、早期疾病复发和早期死亡相关。尽管p53蛋白的积累与肿瘤增殖率有很强的直接相关性，但这两个因素都与预后不良有独立的相关性，提示p53除了调节细胞周期外，可能还有其他生物学功能。意义：当与其他预后因素结合使用时，该测试可以增强我们识别淋巴结阴性乳腺癌患者的能力，这些患者具有早期疾病复发和/或死亡的高风险，对于这些患者，使用辅助化疗是明确合理的。
Background: The p53 (also known as TP53) tumor suppressor gene encodes for a nuclear phosphoprotein thought to regulate proliferation of normal cells. Most p53 mutations result in a nonfunctional protein that accumulates in tumor cell nuclei. These common mutations appear to be involved in the development and/or progression of several neoplastic diseases including human breast cancer. Purpose: Our purpose was to investigate the relationships between levels of mutant p53 protein expression, tumor cell proliferation rate, and clinical outcome in patients with node-negative breast cancer. Methods: Expression of mutant p53 protein was evaluated by frozen-section immunohistochemistry (IHC) and light microscopy in 700 breast cancers from axillary lymph node-negative patients with long-term follow-up (median, 54 months). The immunostaining signal was expressed as the sum of scores representing the proportion and staining intensity of negative and positive tumor cell nuclei (ranges, 0 and 2-8, respectively). Statistical comparisons were made between levels of p53 protein expression and disease-free survival, overall survival, and tumor proliferation rate expressed as the percentage of cells in the S phase (%S phase) as determined by flow cytometry. Results: Of the 700 tumors, 362 (52%) showed, positive nuclear immunostaining (IHC score >0). Proliferation rates were significantly higher (P = .0001) in positive tumors (median %S phase, 7.1%) than in negative tumors (4.1%). In a univariate cutpoint analysis, negative tumors (n = 388) versus low-positive tumors (IHC score = 2-6; n = 263) versus high-positive tumors (IHC score >6; n = 99) showed progressively reduced disease-free survival (80% versus 72% versus 58% at 5 years, respectively; P less-than-or-equal-to .05 for all pairwise comparisons). Analogous results for overall survival were 88% versus 84% versus 74%; only the result for negative versus high positive tumors was significant (P = .003). In a multivariate analysis, expression of p53 protein and high %S phase were independently associated with reduced disease-free survival (P = .008 and .01, respectively). Conclusions: Expression of mutant p53 protein was associated with high tumor proliferation rate, early disease recurrence, and early death in node-negative breast cancer. Despite the strong direct correlation between accumulation of p53 protein and tumor proliferation rate, both factors were independently associated with poor prognosis, suggesting that p53 may have other biological functions in addition to cell-cycle regulation. Implications: This test, when combined with other prognostic factors, may enhance our ability to identify node-negative breast cancer patients at high risk for early disease recurrence and/or death, for whom the use of adjuvant chemotherapy is unequivocally justified.