Abnormal expression of cell cycle regulatory proteins in ductal and lobular carcinomas of the breast
Abnormal expression of cell cycle regulatory proteins in ductal and lobular carcinomas of the breast
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DOI：
10.1038/modpathol.3880172
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发表时间：
2000-09-01
期刊：
影响因子：
7.5
通讯作者：
Ingram, CD
中科院分区：
文献类型：
--
作者：
Geradts, J;Ingram, CD
在之前的一项研究中，我们证明了乳腺癌中的G1细胞周期检查点经常被p16 （CDKN2/INK4A基因的产物）的缺失所取消，并且在较小程度上被pRB（视网膜母细胞瘤基因的产物）的缺失所取消。本研究的目的是确定在保留RE和pie功能的乳腺癌中是否存在细胞周期失调的其他机制。采用优化的免疫组化染色方案，对81例浸润性乳腺癌（导管癌49例，小叶癌26例，混合型6例）石蜡切片进行细胞周期蛋白D1和p53单克隆抗体反应。染色结果与pie、pRB的表达、多种病理参数及DNA倍性相关。25个肿瘤（31%）积累（可能是突变）p53和28个肿瘤（35%）过度表达cyclin D1；7例癌（不包括单纯的小叶癌）异常表达这两种蛋白，p53的积累与核、有丝分裂和总体分级相关，但与肿瘤大小、淋巴结累及或DNA倍性无关。cyclin D1的过表达与任何病理生物学变量无关。pie的缺失与p53的高水平呈负相关，但与细胞周期蛋白D1无关。G1细胞周期检查点（由RE、cyclin D1和pie控制）在65%的癌症中被取消，只有p53在另外17%的癌症中异常。异常表达基因的数量与有丝分裂活性和整体肿瘤分级相关，但与肿瘤组织学、大小或淋巴结状态无关，这表明细胞周期失调是乳腺肿瘤发生的早期事件。只有18%的癌症显示出这四种基因的正常表达水平，p16似乎是细胞周期失调的最常见目标。这些数据表明细胞周期调节蛋白异常在人类乳腺癌中的重要性。
In a previous study, we demonstrated that the G1 cell cycle checkpoint in carcinomas of the breast is frequently abrogated by loss of p16, the product of the CDKN2/INK4A gene, and, to a lesser extent, by loss of pRB, the product of the retinoblastoma gene. The purpose of the present study was to determine whether other mechanisms of cell cycle deregulation exist in breast cancers which have retained RE and pie function. Paraffin sections of 81 invasive breast carcinomas (49 ductal, 26 lobular, 6 mixed) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining results were correlated with the expression of pie and pRB, and with a variety of pathological parameters and DNA ploidy. Twenty-five tumors (31%) accumulated (presumably mutant) p53 and 28 (35%) overexpressed cyclin D1; 7 carcinomas (not including any pure lobular cancers) abnormally expressed both proteins, p53 accumulation correlated with nuclear, mitotic, and overall grade, but not with tumor size, lymph node involvement, or DNA ploidy. Overexpression of cyclin D1 was not associated with any of the patho-biological variables. There was an inverse correlation between loss of pie and high levels of p53, but not cyclin D1. The G1 cell cycle checkpoint, which is controlled by RE, cyclin D1, and pie, was abrogated in 65% of carcinomas, and only p53 was abnormal in an additional 17%. The number of abnormally expressed genes correlated with mitotic activity and overall tumor grade, but not with tumor histology, size, or nodal status, suggesting that cell cycle deregulation is an early event in breast tumorigenesis. Only 18% of the carcinomas showed a normal level of expression of the four genes tested, and p16 appeared to be the most common target of cell cycle deregulation. These data point to the importance of cell cycle regulatory protein abnormalities in human breast cancer.