Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, UAE.
Department of Medical and Clinical Genetics, University of Helsinki, FI-00014 Helsinki, Finland.
Int J Mol Sci. 2020 May 25;21(10):3735. doi: 10.3390/ijms21103735.
There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three common contaminants (BPA; 4-tert-octylphenol, OP; hexabromocyclododecane, HBCD) on mammary epithelial cell (HME1) and MCF7 breast cancer cell line. We also supplied some data on methoxychlor, MXC; 4-nonylphenol, NP; and 2-amino-1-methyl-6-phenylimidazo [4-b] pyridine, PhIP. We focused on testing the prolonged (two months) exposure to low nano-molar concentrations (0.0015-0.0048 nM) presumed to be oncogenic and found that they induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and disrupted the cell cycle. Some agents induced epigenetic (methylation) changes of tumor suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13, and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that these agents increased cellular invasiveness through collagen. Cellular abilities to form colonies in soft agar were increased for MCF7. Toxic agents induced phosphorylation of protein kinase such as EGFR, CREB, STAT6, c-Jun, STAT3, HSP6, HSP27, AMPKα1, FAK, p53, GSK-3α/β, and P70S6 in HME1. Most of these proteins are involved in potential oncogenic pathways. Overall, these data clarify the molecular alterations that can be induced by some common environmental contaminants in mammary epithelial cells which could be a foundation to understand environmental carcinogenesis.
有充分的流行病学证据表明，环境污染物如双酚 A（BPA）在乳腺癌的发展中起作用，但它们的作用机制仍不完全清楚。因此，我们试图分析三种常见污染物（BPA、4-叔辛基苯酚、OP；六溴环十二烷、HBCD）对乳腺上皮细胞（HME1）和 MCF7 乳腺癌细胞系的影响。我们还提供了一些关于甲氧滴滴涕、MXC；4-壬基酚、NP；和 2-氨基-1-甲基-6-苯基咪唑并[4-b]吡啶、PhIP 的数据。我们专注于测试低纳摩尔浓度（0.0015-0.0048 nM）的长时间（两个月）暴露，推测其具有致癌性，发现它们诱导了 DNA 损伤（表现为 pH2A.X、pCHK1、pCHK2、p-P53 的上调）并破坏了细胞周期。一些试剂诱导了肿瘤抑制基因 TIMP3、CHFR、ESR1、IGSF4、CDH13 和 GSTP1 的表观遗传（甲基化）变化。显然，这些分子改变的积累是癌症发展的重要基础。与此一致，我们观察到这些试剂通过胶原蛋白增加了细胞的侵袭性。MCF7 细胞在软琼脂中形成菌落的能力增加。毒性试剂诱导了 EGFR、CREB、STAT6、c-Jun、STAT3、HSP6、HSP27、AMPKα1、FAK、p53、GSK-3α/β 和 P70S6 等蛋白激酶的磷酸化，在 HME1 中。这些蛋白质中的大多数都参与了潜在的致癌途径。总的来说，这些数据阐明了一些常见环境污染物在乳腺上皮细胞中可能引发的分子改变，这可能是理解环境致癌作用的基础。
