乳腺癌（BC）的预后和结果受到肥胖的不利影响。高胰岛素血症常见于肥胖状态，与 BC 较高的死亡和复发风险相关。高达 80% 的 BC 过度表达胰岛素受体 (INSR)，这与较差的预后相关。通过分别生成 MMTV 驱动的多瘤中 T (PyMT) 和 ErbB2/Her2 BC 小鼠模型来测试 INSR 在乳腺肿瘤发生中的作用，并协调乳腺上皮限制性删除 INSR。在这两种模型中，删除一个或两个 INSR 拷贝都会导致肿瘤发生和负担显着延迟。小鼠肿瘤和细胞的纵向表型特征表明，INSR 缺失影响肿瘤的发生，而不是进展和转移。 INSR 在未转化的乳腺上皮细胞中维持生物能表型，与其激酶活性无关。删除一个或两个 INSR 拷贝引起的表型相似，表明 INSR 对乳腺肿瘤发生的影响存在剂量依赖性阈值。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in the obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of BCs overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR's role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR. In both models, deletion of either one or both copies of INSR leads to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumors and cells reveals that INSR deletion affects tumor initiation, not progression and metastasis. INSR upholds a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.