Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
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DOI：
10.1093/carcin/bgs097
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发表时间：
2012-04-01
期刊：
影响因子：
4.7
通讯作者：
Wang, Hwa-Chain R.
中科院分区：
文献类型：
--
作者：
Choudhary, Shambhunath;Sood, Shilpa;Wang, Hwa-Chain R.
超过85%的乳腺癌是散发性的，可归因于长期暴露于环境致癌物，例如饮食中的致癌物，通过从非癌到癌前和恶性阶段的多步骤疾病过程。化学致癌物2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（PhIP）是高温熟肉中发现的最丰富的杂环胺之一，被认为是乳腺癌致癌物。然而，PhIP在乳腺细胞癌变中的作用机制尚不清楚。在这里，我们证明，第一次，在生理上可实现的，皮科纳摩尔浓度的PhIP的累积暴露有效地诱导人乳腺上皮MCF 10A细胞从非癌阶段到癌前和恶性阶段的剂量和剂量依赖性的方式进行性癌变。通过越来越多地获得对生长因子依赖性降低的癌症相关特性、锚定非依赖性生长、腺泡构象破坏、增殖、迁移、侵袭、具有转移的致瘤性和增加的干细胞样细胞群来测量进行性致癌作用。这些生物学变化伴随着生物化学和分子变化，包括H-Ras基因表达上调、细胞外信号调节激酶（ERK）通路激活、Nox-1表达、活性氧（ROS）升高、HIF-1 α、Sp1、肿瘤坏死因子-α、基质金属蛋白酶（MMP）-2、MMP-9、醛脱氢酶活性增加和E-钙粘蛋白减少。Ras-ERK-Nox-ROS通路在PhIP诱导的细胞癌变过程中起重要的启动和维持作用。使用生物学、生物化学和分子变化作为目标终点，我们鉴定了绿色茶儿茶素组分表儿茶素-3-没食子酸酯和表没食子儿茶素-3-没食子酸酯在非细胞毒性剂量下能够抑制PhIP诱导的细胞致癌性和致瘤性。
More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens, such as those in the diet, through a multistep disease process progressing from non-cancerous to premalignant and malignant stages. The chemical carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic amines found in high-temperature cooked meats and is recognized as a mammary carcinogen. However, the PhIP's mechanism of action in breast cell carcinogenesis is not clear. Here, we demonstrated, for the first time, that cumulative exposures to PhIP at physiologically achievable, pico to nanomolar concentrations effectively induced progressive carcinogenesis of human breast epithelial MCF10A cells from a non-cancerous stage to premalignant and malignant stages in a dose- and exposure-dependent manner. Progressive carcinogenesis was measured by increasingly- acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, acinar-conformational disruption, proliferation, migration, invasion, tumorigenicity with metastasis and increased stem-like cell populations. These biological changes were accompanied by biochemical and molecular changes, including upregulated H-Ras gene expression, extracellular signal-regulated kinase (ERK) pathway activation, Nox-1 expression, reactive oxygen species (ROS) elevation, increased HIF-1 alpha, Sp1, tumor necrosis factor-alpha, matrix metalloproteinase (MMP)-2, MMP-9, aldehyde dehydrogenase activity and reduced E-cadherin. The Ras-ERK-Nox-ROS pathway played an important role in not only initiation but also maintenance of cellular carcinogenesis induced by PhIP. Using biological, biochemical and molecular changes as targeted endpoints, we identified that the green tea catechin components epicatechin-3-gallate and epigallocatechin-3-gallate, at non-cytotoxic doses, were capable of suppressing PhIP-induced cellular carcinogenesis and tumorigenicity.