ICMR-National Institute of Nutrition, Hyderabad 500007, India.
UT Southwestern Medical Center, Children Research Institute, Dallas, TX 75390, USA.
Int J Mol Sci. 2023 Jul 14;24(14):11441. doi: 10.3390/ijms241411441.
Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.
患有肥胖症和糖尿病合并症的患者被认为患乳腺癌的风险较高，且乳腺癌结局较差。尽管有几项报告显示肥胖症、糖尿病和糖尿病前期与乳腺癌之间存在强化联系，但潜在的分子机制仍不清楚。本研究旨在使用葡萄糖耐量受损的自发肥胖大鼠模型（WNIN/GR-Ob 大鼠），研究因合并糖尿病或肥胖而导致乳腺癌风险增加的潜在分子联系。在动物 60 天大时，经口给予溶解的 DMBA 混悬液（40mg/kg 体重）单次剂量，以诱导乳腺癌。测量肿瘤发生率、潜伏期、肿瘤频率和肿瘤体积。进行组织学、免疫组织化学和免疫印迹，以评估肿瘤形态和信号分子的表达水平。与对照瘦大鼠相比，GR-Ob 大鼠的乳腺肿瘤发生具有早期发病和潜伏期较短的特点。肥胖大鼠中有 62%发生乳腺肿瘤，而瘦大鼠中仅 21%发生乳腺肿瘤。与瘦大鼠相比，肥胖大鼠肿瘤组织中 ER、PR、Ki67 和 p53 标志物的过度表达。与瘦大鼠相比，肥胖大鼠乳腺肿瘤中涉及 IGF-1/PI3K/Akt/GSK3β/β-catenin 信号通路分子的细胞增殖和血管生成特征的标志物水平上调。此外，肥胖伴糖尿病前期与 IGF-1 信号的变化有关，并作用于 PI3K/Akt/GSK3β/β-catenin 信号，导致肥胖大鼠比瘦大鼠的细胞增殖更快，乳腺肿瘤发展更快。这些结果表明，葡萄糖耐量受损的自发肥胖大鼠模型中的肿瘤起始和发展比其瘦型大鼠更快。
