Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer:: The role of promoter methylation of TSC genes
Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer:: The role of promoter methylation of TSC genes
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DOI：
10.1016/j.ejca.2005.03.023
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发表时间：
2005-07-01
影响因子：
8.4
通讯作者：
Mansel, RE
中科院分区：
文献类型：
--
作者：
Jiang, WG;Sampson, J;Mansel, RE
目的：结节性硬化症（TSC）基因TSC1和TSC2分别编码蛋白产物错构体和结节蛋白，是推测的肿瘤抑制基因。TSC基因的种系突变可导致遗传性疾病TSC的发生。这种疾病的特点是在许多器官中发生错构瘤，并与增殖性肺病、淋巴管平滑肌瘤病、脑肿瘤巨细胞星形细胞瘤和偶尔与肾细胞癌有关。然而，TSC基因尚未在乳腺癌中得到研究。本研究旨在探讨TSC基因产物在人乳腺癌细胞和组织中的表达及其异常的潜在机制。实验设计和结果：免疫组化分析发现，在正常乳腺上皮细胞中，错构体和tuberin被强烈染色，而在基质细胞中，错构体和tuberin被微弱染色。而在侵袭性肿瘤组织中，两种蛋白的染色均明显降低（P < 0.01）。在信息水平上，虽然正常组织和肿瘤组织均表达TSC产物，但肿瘤组织中tuberin的转录水平明显低于正常组织（P < 0.05）。结阴性肿瘤与结阳性肿瘤合并错构体和tuberin的差异无统计学意义。与未患病的患者相比，复发和死于乳腺癌的患者肿瘤中的结节素水平明显较低（P分别= 0.03和0.05）。同样，与没有疾病的患者相比，有转移、复发和死亡的患者的错构体水平显著降低（P分别为0.001、0.041和0.003）。通过甲基化特异性PCR，发现TSC1启动子在ZR751、MDA、MB 435和BT549中重度甲基化，但在表达高水平错构体的MCF-7中没有甲基化。TSC1启动子甲基化也见于大多数乳腺肿瘤，但仅见于有限数量的正常组织。TSC2启动子的甲基化似乎不太频繁。发现MDA MB 468、MDA NIB 483、MDA MB 435S和弱MDA MB 435有TSC2启动子甲基化。然而，在乳腺组织中，发现极少量样本具有TSC2启动子甲基化。结论：TSC1基因在人乳腺癌细胞系和乳腺肿瘤组织中存在异常表达，其启动子在乳腺肿瘤组织中存在甲基化。在乳腺癌患者中，TSC1的表达与不利的临床结果相关。(c) 2005 Elsevier Ltd版权所有。
Purpose: The tuberous sclerosis (TSC) genes TSC1 and TSC2 encode the protein products hamartin and tuberin, respectively, and are putative tumour suppressor genes. Germ-line mutation of either TSC gene leads to the development of the heritable disorder TSC. This disorder is characterized by the development of hamartomas in many organs and is associated with the proliferative lung disease, lymphangioleiomyomatosis, the brain tumour giant cell astrocytoma and occasionally with renal cell carcinoma. However, the TSC genes have not been studied in breast cancer. The current study investigated the expression of the TSC gene products and the potential mechanisms of their aberrancy in human breast cancer cells and tissues.Experimental design and results: Using immunohistochemical analysis, both hamartin and tuberin were found to be strongly stained in normal mammary epithelial cells and weakly in stromal cells. In invasive tumour tissues, however, the staining of both proteins were to be markedly reduced (P < 0.01). At message level, although normal and tumour tissues expressed both TSC products, the transcript levels of tuberin was significantly lower in tumour tissues compared with normal tissues (P < 0.05). There was no statistical difference between node negative and node positive tumours with both hamartin and tuberin. Tumours from patients who developed recurrence and died from breast cancer had significantly low levels of tuberin compared with those who remained disease free (P = 0.03 and 0.05, respectively). Likewise, hamartin levels were significantly lower in patients with metastasis, recurrence and mortality, when compared with those remained disease free (P = 0.001, 0.041 and 0.003, respectively). Using methylation specific PCR, the TSC1 promoter was found to be heavily methylated in ZR751, MDA MB 435, and BT549, but not in MCF-7 which expressed highly level of hamartin. TSC1 promoter methylation was also seen in most breast tumours, but only in a limited number of normal tissues. The methylation of TSC2 promoter appears to be less frequent. MDA MB 468, MDA NIB 483, MDA MB 435S and weakly MDA MB 435 were found to have methylated TSC2 promoter. In breast tissues, however, a very small number of samples were found to have methylation of the TSC2 promoter.Conclusion: TSC1 genes are aberrantly expressed in human breast cancer cell lines and breast tumour tissues and their promoters are seen to be methylated in breast tumour tissues. The expression of TSC1 is associated with an unfavourable clinical outcome in patients with breast cancer. (c) 2005 Elsevier Ltd. All rights reserved.