Department of Physiology & Biophysics, Department of Pediatrics and Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Department of Pediatrics and Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Carcinogenesis. 2014 Sep;35(9):2102-12. doi: 10.1093/carcin/bgu106. Epub 2014 May 15.
Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.
许多成人慢性病被认为在生命早期受到母体营养的影响，但潜在机制在很大程度上仍不清楚。与肥胖相关的疾病可能部分是由于高脂肪摄入。在此，我们评估了在妊娠和哺乳期暴露于高脂肪饮食（HFD）或对照饮食（CD）（分别为脂肪的 45%和 17%卡路里）的雌性小鼠乳腺肿瘤病毒-Wnt-1 转基因（Tg）后代中的乳腺肿瘤风险，断奶后为后代提供 CD。在 Tg 后代中，母体 HFD 暴露增加了乳腺肿瘤的发生率并降低了肿瘤潜伏期，而不影响肿瘤体积。肿瘤风险与血清中更高的肿瘤坏死因子-α和胰岛素以及氧化应激生物标志物的改变相关，并且与与肿瘤促进（白细胞介素 6（Il6））或抑制（磷酸酶和张力蛋白同源物缺失于染色体 10（Pten），B 细胞淋巴瘤 2（Bcl2））相关的乳腺基因表达的早期变化相关。暴露于母体 HFD 的相应野生型后代显示出加速的乳腺发育、更高的乳腺脂肪含量、增加的胰岛素抵抗和 Pten、Bcl2 和 Il6 的早期变化，而与 CD 暴露的后代相比。与 CD 喂养的对应物相比，喂养 HFD 的母鼠显示出更高的血清葡萄糖和氧化应激生物标志物，但肥胖程度相当。在人类乳腺癌 MCF-7 细胞中，来自母体 HFD 暴露的 Tg 后代的血清引起了 PTEN、BCL2 和 IL6 基因表达的变化，模拟了体内暴露；增加了细胞活力和乳腺球体形成，并诱导了胰岛素敏感性的措施（胰岛素受体底物-1（IRS-1）、IRS-2）。外源性胰岛素和 PTEN 特异性抑制剂 SF1670 重现了血清对 IRS-1 的作用。因此，高胰岛素血症和 PTEN 功能丧失可能通过增加后代乳腺 IRS-1 表达将母体 HFD 暴露与增强的胰岛素敏感性联系起来，从而促进乳腺癌风险。
