More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk-Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk-Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy.

译文

超过85% 的乳腺癌是零星的,可归因于长期暴露于环境致癌物和共致癌物。为了鉴定具有诱导细胞前恶性肿瘤能力的共致癌物,我们研究了三氯卡班 (TCC) 的活性,三氯卡班是一种常用于家庭和个人护理产品的抗菌剂。在这里,我们首次证明了以生理上可达到的纳摩尔浓度长期暴露于TCC会导致人类乳腺细胞从非癌性到恶变前的进行性癌变。通过日益获得的与癌症相关的特性来衡量恶性癌前的发生,这些特性减少了对生长因子的依赖性,不依赖锚定的生长和细胞增殖的增加,而没有获得细胞致瘤性。长期TCC暴露还会诱导Erk-Nox途径的组成型激活和细胞中活性氧 (ROS) 的增加。单次TCC暴露不仅在非癌性乳腺细胞中而且在乳腺癌细胞中诱导了Erk-Nox途径的瞬时诱导,ROS升高,细胞增殖增加和DNA损伤。使用这些组成性和瞬时诱导的变化作为终点,我们揭示了非细胞毒性姜黄素可有效干预TCC诱导的细胞前恶性肿瘤。我们的结果使我们建议在流行病学研究中应认真考虑TCC的共同致癌潜力,以揭示TCC在散发性乳腺癌发展中的重要性。使用TCC诱导的瞬时终点和组成型终点作为靶标可能有助于识别非细胞毒性的预防剂,例如姜黄素,可有效抑制TCC诱导的细胞前恶性肿瘤。

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