Obesity and p16INK4A Downregulation Activate Breast Adipocytes and Promote Their Protumorigenicity
Obesity and p16INK4A Downregulation Activate Breast Adipocytes and Promote Their Protumorigenicity
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DOI：
10.1128/mcb.00101-17
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发表时间：
2017-09-01
影响因子：
5.3
通讯作者：
Aboussekhra, Abdelilah
中科院分区：
文献类型：
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作者：
Al-Khalaf, Huda H.;Amir, Mrad;Aboussekhra, Abdelilah
肥胖越来越被认为是乳腺癌发展的一个危险因素。然而，肥胖相关的乳腺癌发生的分子基础仍然难以捉摸。在这项研究中，我们已经表明，肥胖症降低了乳腺脂肪细胞中的肿瘤抑制因子p16（INK 4A）蛋白的水平，与瘦女性的成熟脂肪细胞相比，乳腺脂肪细胞在体外和原位肿瘤异种移植物中显示出活性特征和强的致癌潜力。此外，肥胖引发了乳腺导管上皮细胞的上皮间质转化（EMT）。有趣的是，p16（INK 4A）的特异性下调增加了各种脂肪因子（包括瘦素）的表达/分泌水平，并激活了瘦女性的乳腺脂肪细胞。因此，与肥胖女性的乳腺脂肪细胞一样，p16缺陷型脂肪细胞以瘦素依赖的方式诱导正常原代乳腺腔细胞发生EMT，并增强肿瘤生长。此外，我们已经表明，p16（INK 4A）通过microRNAs 141和146 b-5 p（miR-141和miR-146 b-5 p）在mRNA水平上负控制瘦素，它们在3'非翻译区（UTR）的特定序列处结合瘦素mRNA。这些结果表明，肥胖通过p16下调激活乳腺基质脂肪细胞，p16上调瘦素并促进前致癌过程。
Obesity is increasingly recognized as a risk factor for breast cancer development. However, the molecular basis of obesity-related breast carcinogenesis remains elusive. In this study, we have shown that obesity reduces the level of the tumor suppressor p16(INK4A) protein in breast adipocytes, which showed active features and strong procarcinogenic potential both in vitro and in orthotopic tumor xenografts compared to mature adipocytes from lean women. Furthermore, obesity triggered epithelial-to-mesenchymal transition (EMT) in breast ductal epithelial cells. Interestingly, specific downregulation of p16(INK4A) increased the expression/secretion levels of various adipokines, including leptin, and activated breast adipocytes from lean women. Consequently, like breast adipocytes from obese women, p16-deficient adipocytes induced EMT in normal primary breast luminal cells in a leptin-dependent manner and enhanced tumor growth. Additionally, we have shown that p16(INK4A) negatively controls leptin at the mRNA level through microRNAs 141 and 146b-5p (miR-141 and miR-146b-5p), which bind the leptin mRNA at a specific sequence in the 3' untranslated region (UTR). These results show that obesity activates breast stromal adipocytes through p16 downregulation, which upregulates leptin and promotes procarcinogenic processes.