Breast cancer and thyroid dysfunctions have been associated for decades. Although many studies suggest a biological correlation, the mechanisms linking these two pathologies have not been elucidated. Reactive oxygen species (ROS) can oxidize lipids, proteins, and DNA molecules and may promote tumor initiation. Hence, we aimed at evaluating the mammary redox balance and genomic instability in a model of experimental hypothyroidism. Female Wistar rats were treated with 0.03% methimazole for 7 or 21 days to evaluate ROS generation, antioxidant enzyme activities, and oxidative stress biomarkers, as well as genomic instability. After 7 days, lower catalase, GPX, and DUOX activities were detected in the breast of hypothyroid group compared to the control while the levels of 4-hydroxynonenal (HNE) were higher. In addition, hypothyroid group showed an increase in γH2Ax/H2Ax ratio. Twenty-one days hypothyroid group had increased catalase and SOD activities, without significant differences between groups in the levels of oxidative stress biomarkers and DNA damage. TSH-treated MCF10A cells showed a higher extracellular, intracellular, and mitochondrial ROS production. Additionally, greater DNA damage was observed in these cells, demonstrated by a higher comet tail DNA percentage and increased 53BP1 foci. Finally, we found that TSH treatment was not able to alter cell viability. The Genome Cancer Atlas (TGCA) data showed that high TSHR expression is associated with more invasive breast cancer types. In conclusion, we demonstrate that oxidative stress and DNA damage in breast are early events of experimental hypothyroidism. Moreover, high TSH levels induce oxidative stress and genomic instability in mammary cells.

中文翻译：

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甲状腺功能减退会导致乳房发生氧化应激和 DNA 损伤。

几十年来，乳腺癌和甲状腺功能障碍一直存在关联。尽管许多研究表明存在生物学相关性，但尚未阐明将这两种病理联系起来的机制。活性氧 (ROS) 可以氧化脂质、蛋白质和 DNA 分子，并可能促进肿瘤发生。因此，我们旨在评估实验性甲状腺功能减退模型中的乳腺氧化还原平衡和基因组不稳定性。雌性 Wistar 大鼠用 0.03% 甲巯咪唑处理 7 或 21 天，以评估 ROS 生成、抗氧化酶活性、氧化应激生物标志物以及基因组不稳定性。7天后，甲减组乳腺中过氧化氢酶、GPX和DUOX活性低于对照组，而4-羟基壬烯醛（HNE）水平较高。此外，甲状腺功能减退组显示 γH2Ax/H2Ax 比值增加。21天甲减组过氧化氢酶和SOD活性增加，组间氧化应激生物标志物和DNA损伤水平无显着差异。TSH 处理的 MCF10A 细胞显示出更高的细胞外、细胞内和线粒体 ROS 产生。此外，在这些细胞中观察到更大的 DNA 损伤，表现为彗尾 DNA 百分比更高和 53BP1 病灶增加。最后，我们发现 TSH 处理不能改变细胞活力。基因组癌症图谱 (TGCA) 数据显示，高 TSHR 表达与更具侵袭性的乳腺癌类型相关。总之，我们证明乳房中的氧化应激和 DNA 损伤是实验性甲状腺功能减退的早期事件。而且，