Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
JCI Insight. 2023 Dec 8;8(23):e170105. doi: 10.1172/jci.insight.170105.
Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.
糖尿病通常会影响癌症患者。我们通过分析原位人肿瘤异种移植物、患者肿瘤和暴露于糖尿病/高血糖样条件下的乳腺癌细胞，采用三管齐下的方法研究了糖尿病对乳腺癌生物学的影响。我们旨在通过研究代谢组、转录组和肿瘤突变负担来确定共同的表型和分子特征。糖尿病和高血糖并未促进细胞增殖，而是诱导了与迁移率和转移几率增加相关的间充质和干细胞样表型。它们还促进了活性氧的形成以及与 DNA 修复缺陷相关的转录组和突变特征。此外，在存在糖尿病的情况下，食物和微生物组衍生的代谢物往往会在乳腺肿瘤中积累，从而可能影响肿瘤生物学。在高血糖样条件下培养的乳腺癌细胞获得了更多的 DNA 损伤，并对 DNA 修复抑制剂更敏感。基于这些观察结果，我们得出结论，与糖尿病相关的乳腺癌肿瘤可能对 DNA 损伤修复抑制剂表现出更高的药物反应。
