Anticancer Molecular Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, USA.
Carcinogenesis. 2012 Apr;33(4):876-85. doi: 10.1093/carcin/bgs097. Epub 2012 Feb 3.
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-1α, Sp1, tumor necrosis factor-α, 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.
超过 85%的乳腺癌是散发性的，归因于长期暴露于环境致癌物，如饮食中的致癌物，通过一个多步骤的疾病过程从非癌前病变进展到癌前病变和恶性阶段。化学致癌物 2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）是高温烹饪肉类中发现的最丰富的杂环胺之一，被认为是一种乳腺致癌物。然而，PhIP 在乳腺癌细胞癌变中的作用机制尚不清楚。在这里，我们首次证明，生理上可达到的皮摩尔至纳摩尔浓度的 PhIP 累积暴露以剂量和暴露依赖性方式有效地诱导人乳腺上皮 MCF10A 细胞从非癌前病变阶段向癌前病变和恶性阶段的进行性致癌作用。进行性致癌作用通过逐渐获得的癌症相关特性来衡量，包括对生长因子的依赖性降低、非锚定依赖性生长、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体。这些生物学变化伴随着生化和分子变化，包括 H-Ras 基因表达上调、细胞外信号调节激酶（ERK）途径激活、Nox-1 表达、活性氧（ROS）升高、HIF-1α、Sp1、肿瘤坏死因子-α、基质金属蛋白酶（MMP）-2、MMP-9、醛脱氢酶活性和 E-钙粘蛋白减少。Ras-ERK-Nox-ROS 途径不仅在 PhIP 诱导的细胞癌变的起始中而且在维持中都起着重要作用。使用生物、生化和分子变化作为靶向终点，我们确定了绿茶儿茶素成分表儿茶素-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 诱导的细胞癌变和致瘤性。
