Peixoto Milena Simões, de Vasconcelos E Souza Andressa, Andrade Iris Soares, de Carvalho El Giusbi Carolina, Coelho Faria Caroline, Hecht Fabio, Miranda-Alves Leandro, Ferreira Andrea Claudia Freitas, Carvalho Denise Pires, Fortunato Rodrigo S
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Endocr Relat Cancer. 2021 Jun 20;28(7):505-519. doi: 10.1530/ERC-21-0010.
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.
几十年来，乳腺癌与甲状腺功能障碍一直存在关联。尽管许多研究表明二者存在生物学相关性，但连接这两种病理状态的机制尚未阐明。活性氧（ROS）可氧化脂质、蛋白质和DNA分子，并可能促进肿瘤的发生。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。用0.03%甲巯咪唑处理雌性Wistar大鼠7天或21天，以评估ROS的产生、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，与对照组相比，甲状腺功能减退组乳腺中的过氧化氢酶、谷胱甘肽过氧化物酶（GPX）和双氧化酶（DUOX）活性降低，而4-羟基壬烯醛（HNE）水平升高。此外，甲状腺功能减退组的γH2Ax/H2Ax比值增加。甲状腺功能减退21天组的过氧化氢酶和超氧化物歧化酶（SOD）活性增加，两组在氧化应激生物标志物水平和DNA损伤方面无显著差异。促甲状腺激素（TSH）处理的MCF10A细胞表现出更高的细胞外、细胞内和线粒体ROS产生。此外，这些细胞中观察到更大的DNA损伤，表现为彗星尾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，高促甲状腺激素受体（TSHR）表达与更具侵袭性的乳腺癌类型相关。总之，我们证明乳腺中的氧化应激和DNA损伤是实验性甲状腺功能减退的早期事件。此外，高TSH水平会诱导乳腺细胞中的氧化应激和基因组不稳定性。
