Histologically normal human mammary epithelia with silenced p16INK4a overexpress COX-2, promoting a premalignant program
Histologically normal human mammary epithelia with silenced p16INK4a overexpress COX-2, promoting a premalignant program
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DOI：
10.1016/s1535-6108(04)00023-6
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发表时间：
2004-03-01
期刊：
影响因子：
50.3
通讯作者：
Tlsty, TD
中科院分区：
文献类型：
--
作者：
Crawford, YG;Gauthier, ML;Tlsty, TD
在体内和体外，健康女性的乳腺组织中都含有p16(INK4a)启动子高甲基化的变异乳腺上皮细胞(VHMEC)。当继续培养时，vHMEC获得端粒功能障碍，并产生癌症前病变中看到的类型的染色体异常。我们发现，晚期传代的vHMEC表达升高的前列腺素环氧合酶-2(COX-2)，这有助于增加前列腺素合成、血管生成活性和侵袭能力。这些数据表明，人类乳腺上皮细胞的存在有可能获得与恶性细胞相关的多种基因组变化和表型。此外，COX-2的过度表达与体内p16(INK4a)高甲基化的焦点区域一致，创造了理想的乳腺癌前驱候选基因。在体外暴露于COX-2抑制剂后，这些假定的前体可以被选择性地消除。
Breast tissue from healthy women contains variant mammary epithelial cells (vHMEC) exhibiting p16(INK4a) promoter hypermethylation both in vivo and in vitro. When continuously cultured, vHMEC acquire telomeric dysfunction and produce the types of chromosomal abnormalities seen in premalignant lesions of cancer. We find that late passage vHMEC express elevated prostaglandin cyclo-oxygenase 2 (COX-2), which contributes to increased prostaglandin synthesis, angiogenic activity, and invasive ability. These data demonstrate the existence of human mammary epithelial cells with the potential to acquire multiple genomic alterations and phenotypes associated with malignant cells. Moreover, COX-2 overexpression coincides with focal areas of p16(INK4a) hypermethylation in vivo, creating ideal candidates as precursors to breast cancer. These putative precursors can be selectively eliminated upon exposure to COX-2 inhibitors in vitro.