ter Braak Bas, Siezen Christine, Speksnijder Ewoud N, Koedoot Esmee, van Steeg Harry, Salvatori Daniela C F, van de Water Bob, van der Laan Jan Willem
Breast Cancer Res. 2015 Feb 18;17(1):14. doi: 10.1186/s13058-015-0518-y.
Insulin analogues are structurally modified molecules with altered pharmaco-kinetic and -dynamic properties compared to regular human insulin used by diabetic patients. While these compounds are tested for undesired mitogenic effects, an epidemiological discussion is ongoing regarding an association between insulin analogue therapy and increased cancer incidence, including breast cancer. Standard in vivo rodent carcinogenesis assays do not pick up this possible increased carcinogenic potential.
Here we studied the role of insulin analogues in breast cancer development. For this we used the human relevant mammary gland specific p53R270H/⁺WAPCre mouse model. Animals received life long repeated treatment with four different insulin (-like) molecules: normal insulin, insulin glargine, insulin X10 (AspB10) or insulin-like growth factor 1 (IGF1).
Insulin-like molecules with strong mitogenic signaling, insulin X10 and IGF1, significantly decreased the time for tumor development. Yet, insulin glargine and normal insulin, did not significantly decrease the latency time for (mammary gland) tumor development. The majority of tumors had an epithelial to mesenchymal transition phenotype (EMT), irrespective of treatment condition. Enhanced extracellular signaling related kinase (Erk) or serine/threonine kinase (Akt) mitogenic signaling was in particular present in tumors from the insulin X10 and IGF1 treatment groups.
These data indicate that insulin-like molecules with enhanced mitogenic signaling increase the risk of breast cancer development. Moreover, the use of a tissue specific cancer model, like the p53R270H/⁺WAPCre mouse model, is relevant to assess the intrinsic pro-carcinogenic potential of mitogenic and non-mitogenic biologicals such as insulin analogues.
胰岛素类似物是结构经过修饰的分子，与糖尿病患者使用的常规人胰岛素相比，其药代动力学和药效学特性有所改变。虽然这些化合物已针对不良促有丝分裂作用进行了测试，但关于胰岛素类似物治疗与包括乳腺癌在内的癌症发病率增加之间的关联，正在进行流行病学讨论。标准的体内啮齿动物致癌试验无法检测到这种可能增加的致癌潜力。
在此，我们研究了胰岛素类似物在乳腺癌发展中的作用。为此，我们使用了与人类相关的乳腺特异性p53R270H/⁺WAPCre小鼠模型。动物接受了四种不同胰岛素（样）分子的终身重复治疗：正常胰岛素、甘精胰岛素、胰岛素X10（AspB10）或胰岛素样生长因子1（IGF1）。
具有强烈促有丝分裂信号的胰岛素样分子，胰岛素X10和IGF1，显著缩短了肿瘤发生时间。然而，甘精胰岛素和正常胰岛素并未显著缩短（乳腺）肿瘤发生的潜伏期。无论治疗条件如何，大多数肿瘤具有上皮-间质转化表型（EMT）。增强的细胞外信号调节激酶（Erk）或丝氨酸/苏氨酸激酶（Akt）促有丝分裂信号尤其存在于胰岛素X10和IGF1治疗组的肿瘤中。
这些数据表明，具有增强促有丝分裂信号的胰岛素样分子会增加乳腺癌发展的风险。此外，使用组织特异性癌症模型，如p53R270H/⁺WAPCre小鼠模型，对于评估有丝分裂和无丝分裂生物制剂（如胰岛素类似物）的内在致癌潜力是有意义的。
