Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, Netherlands.
BMC Cancer. 2018 Feb 27;18(1):224. doi: 10.1186/s12885-018-4072-8.
The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues).
Immunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms.
We found no significant differences in expression of any of the proteins in breast tumors of women with (n = 211) and without diabetes (n = 101). Among women with diabetes, insulin use (n = 53) was significantly associated with higher tumor protein expression of IGF1R (OR = 2.36; 95%CI:1.02-5.52; p = 0.04) and p-mTOR (OR = 2.35; 95%CI:1.13-4.88; p = 0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p = 0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR = 5.10; 95%CI:1.36-19.14; p = 0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated.
In our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials.
胰岛素受体（INSR）和胰岛素生长因子 1 受体（IGF1R）在糖尿病和乳腺癌的发病机制中都起着重要作用。我们旨在评估患有或不患有糖尿病的女性的乳腺癌肿瘤中与 PI3K 和 MAPK 通路有关或相关的激素和胰岛素相关蛋白的表达情况，以及这些女性是否接受胰岛素（类似物）治疗。
对 2000-2010 年间随机选择的丹麦乳腺癌队列中 312 名患有浸润性乳腺癌的女性的肿瘤组织进行了免疫组织化学染色，这些女性患有或不患有糖尿病。患有糖尿病的女性按照发病年份和乳腺癌诊断时的年龄与不患有糖尿病的女性进行 2:1 频率匹配。成功对肿瘤微阵列进行了 p-ER、EGFR、p-ERK1/2、p-mTOR 和 IGF1R 的染色，并由一位乳腺病理学家进行评分。通过多变量逻辑回归调整绝经和 BMI，评估这些蛋白的表达与糖尿病、胰岛素治疗（人胰岛素和胰岛素类似物）和其他糖尿病药物的相关性；通过交互项评估绝经状态、BMI 和 ER 状态的效应修饰。
我们发现患有糖尿病（n=211）和不患有糖尿病（n=101）的女性的乳腺癌肿瘤中任何一种蛋白的表达均无显著差异。在患有糖尿病的女性中，胰岛素使用（n=53）与 IGF1R（OR=2.36；95%CI：1.02-5.52；p=0.04）和 p-mTOR（OR=2.35；95%CI：1.13-4.88；p=0.02）的肿瘤蛋白表达较高显著相关，尤其是在接受胰岛素类似物治疗的女性中。绝经似乎改变了胰岛素与 IGF1R 表达之间的关联（p=0.07）；仅在绝经前女性的肿瘤中观察到 IGF1R 表达的差异（OR=5.10；95%CI：1.36-19.14；p=0.02）。我们没有发现其他类型的糖尿病药物（如二甲双胍）与评估的五种蛋白的表达之间存在关联。
在我们的研究中，患有糖尿病的女性的乳腺癌肿瘤并没有表现出选定的 PI3K/MAPK 通路相关蛋白表达的改变。我们观察到胰岛素治疗与乳腺癌肿瘤中 p-mTOR 和 IGF1R 表达增加之间的关联，尤其是在绝经前女性中。如果得到证实，这种观察结果可能具有临床意义，因为目前正在临床试验中研究 IGF1R 和 mTOR 抑制剂的使用。
